Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:40]=[CH:39][C:27]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][C:24]2[CH:40]=[CH:39][C:27]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35](=[O:37])(=[O:36])[NH2:38])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Nc1ccc(Oc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc(Oc5ccc(S(N)(=O)=O)cc5)cc4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(4-sulphamoylphenoxy)phenyl-]1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(4-aminophenoxy)phenylsulphonamide using method I. LCMS; retention time 3.38 min, MH+ 541.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([OH:34])[CH:33]=1)[C:28](O)=[O:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:28](=[O:29])[C:27]2[CH:26]=[C:25]([OH:24])[CH:33]=[C:32]([OH:34])[CH:31]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3cc(O)cc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 3,5-dihydroxybenzoic acid as brown solid (37%). MS 454 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[C:22]=2[CH3:23])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:21])=[CH:16][C:15]=3[C:22]=2[CH3:23])[CH2:7][CH2:6]1
Reactant: Cc1c(N2CCN(Cc3c(Cl)cccc3Cl)CC2)ccc2oc(C(=O)O)cc12
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(N2CCN(Cc3c(Cl)cccc3Cl)CC2)ccc2oc(C(=O)N3CCOCC3)cc12
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
To a solution of 5-[4-(2,6-Dichloro benzyl)-piperazine-1-yl]-4-methyl-benzofuran-2-carboxylic acid (0.07 g, 0.00017 mol) in anhydrous DMF (275 ml) was added diisopropyl ethyl amine (0.08 ml, 0.0005 mol) and morpholine (0.16 ml, 0.00018 mol) under nitrogen atmosphere. The reaction mixture was stirred for 15 minutes, added Py-BOP (0.11 g, 0.0002 mol) and stirred for 1 hour. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched into ice water. The solid separated was filtered. After drying under vacuum, the crude product was isolated as white solid. The crude product was purified by Prep HPLC using a Zorbax C-18 column with mobile phase 0.1% trifluoroacetic acid in water (A)/Acetonitrile (B) with a flow rate of 20 ml/min to yield {5-[4-(2,6-dichlorobenzyl)piperazine-1-yl]-4-methyl-benzofuran-2-yl}-morpholin-4-yl-methanone (35 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=[CH:17][C:16]=4[N:25]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N+:18]([O-:36])=[CH:17][C:16]=4[N:25]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccc(F)cc1)COC3
Reaction time: 8 h
Yield: 100 %

Procedure:
(11S)-11-{[(4-Fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (700 mg, 1.93 mmol) was dissolved in 25 mL of CHCl3 and treated with MCPBA (570 mg, 77% max). The reaction was allowed to stir overnight and then 10 mL of aqueous 2% Na2CO3 solution was added and the layers were separated. The aqueous portion was extracted with CHCl3 (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (11S)-11-{[(4-fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (732 mg) as an orange foam.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:22]([C:19]1([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH2:21][CH2:20]1)=[O:23]
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: Nc1nc2ccccc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3nc4ccccc4s3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
Benzothiazol-2-ylamine (30. mg, 0.20 mmol) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (38 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) containing triethylamine (84 μL, 0.60 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 80 mg, 0.21 mmol) was added and the solution was allowed to stir at room temperature for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (17 mg, 0.052 mmol, 26%). ESI-MS m/z calc. 324.1. found 325.0 (M+1)+. Retention time of 3.48 minutes.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:13]=1[NH2:22]>>[Cl:18][C:17]1[C:16]([Cl:19])=[C:15]([Cl:20])[C:14]([Cl:21])=[C:13]2[C:12]=1[NH:11][C:2](=[O:4])[C:1](=[O:8])[NH:22]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1c(N)c(Cl)c(Cl)c(Cl)c1Cl
Product: O=c1[nH]c2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrachloro-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.97 g, 20.0 mmol) and 1,2-diamino-3,4,5,6-tetrachlorobenzene (500 mg, 2.03 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the orange solid collected by vacuum filtration and rinsed with cold EtOH (10 mL) and air dried. This solid was recrystallized from abs. ethanol to give 97.0 mg (16%) of an orange solid mp 326°-328° C. (dec). (Lit., >360° ). FT-IR: 3198, 3135 cm-1 (N-H), 1750, 1623 cm-1 (C=O). 1H NMR δ (d6 -DMSO) δ 11.7 (br s, 2H, N-H) EIMS m/z 306 (M+8, 1.7), 304 (M+6, 11.5), 302 (M+4, 47.4), 300 (M+2, 93.9), 288 (M+, 76.7), 274 (50.0), 272 (bp), 270 (79.0), 209 (61.0), 207 (64.0). EIHRMS calc. for C8H2Cl4N2O2 297.8870, found 297.8864.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+].Cl>CS(C)=O>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
n-Octyl bromide (1.63 mL) was added to a solution of 4-(4'-hydroxyphenyl)benzoic acid (2.02 g) and 5N sodium hydroxide (3.77 mL) in dimethylsulfoxide (25 mL) and the mixture was stirred at 60°-70° C. for a period of 18 hours. The reaction mixture was cooled to room temperature and then acidified with approximately 6 mL of 2N HCl and partitioned between ethyl acetate and water. The organic phase was washed with 3×250 mL of water and 1×250 mL brine and filtered. The filter cake was saved. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain the 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylic acid (1.54 g). The filter cake from above was washed with dichloromethane and traces of the organic solvent were removed under reduced pressure to yield 1.53 g of product. The material was combined to yield a total of 3.07 g of 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 0.87 (t, 3H), 1.29 (m, 8H), 1.41 (m, 2H), 1.72 (m, 2H), 4.01 (t, 2H), 7.03 (d, 2H), 7.68 (d, 2H), 7.73 (d, 2H), 7.98 (d, 2H).
Reaction SMILES: Cl[C:2]1[S:6][CH:5]=[CH:4][C:3]=1[CH2:7]Br.[Cl-].C[N+](C(=O)CCCCCCC)(C(=O)CCCCCCC)[C:12](=O)[CH2:13][CH2:14]CCCCC.C(Cl)(Cl)Cl>O1CCCC1.[OH-].[Na+]>[S:6]1[CH:5]=[CH:4][C:3]2[CH:7]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC
Reactant: Clc1sccc1CBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: c1ccc2sccc2c1

Procedure:
Stir cis-6-chloro-2,3-dihydro-3-hydroxy-2-[(1', 2', 4'-triazolyl)-1'-methyl]benzo(b)thiophene (1.17 gms., 4.37 mmols), 2-chloro-3-thenylbromide (1.06 gms., 5.0 mmol) and methyl tricaprylyl ammonium chloride (0.1 gm.) in tetrahydrofuran (25 ml) and 50% sodium hydroxide (10 ml) at room temperature for one hour. Pour the reaction mixture into chloroform (500 ml.) and extract with two 500 ml. portions of water. Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo. Chromatograph the resultant residue on silica gel eluting with chloroform. Combine the like eluates as determined by thin layer chromatography and evaporate in vacuo to obtain cis-6-chloro-3-(2'-chloro-3'-thenyloxy)-2,3-dihydro-2-[(1", 2", 4"-triazolyl)-1"-methyl]benzo(b)thiophene, a gum.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][C@@H:11]([CH2:14][OH:15])[C@H:10]([OH:16])[CH2:9]2)C=CC=CC=1>CO.[Pd]>[OH:16][C@H:10]1[C@H:11]([CH2:14][OH:15])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OC[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Agent: [Pd]
Solvent: CO
Product: OC[C@@H]1CCNC[C@H]1O
Yield: 107.6 %

Procedure:
A mixture of (±)-trans-1-(phenylmethyl)-3-hydroxy-4-piperidinemethanol (17.8 g, 0.085 mol) (already described in J. Med. Chem., 16, pp. 156-159 (1973)) in methanol (250 ml) was hydrogenated, at 50° C., with palladium on activated carbon (10%, 2 g) as catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding 12 g of (±)-trans-3-hydroxy-4-piperidinemethanol (interm. 1-a) (used in next reaction step without further purification). The corresponding cis-isomer is known from J. Org. Chem., 34, pp. 3674-3676 (1969).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2([CH3:26])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH:14]2[CH3:25])[CH:10]=[CH:11][CH:12]=1)=O.O.[NH2:29]N>CO.O>[CH2:19]([N:16]1[CH2:17][CH2:18][C:13]([CH3:26])([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[CH:4]=[CH:3][NH:2][N:29]=3)[CH:8]=2)[CH:14]([CH3:25])[CH2:15]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: NN
Reactant: CCCCCCN1CCC(C)(c2cccc(C(=O)C=CN(C)C)c2)C(C)C1
Solvent: CO
Solvent: O
Product: CCCCCCN1CCC(C)(c2cccc(-c3cc[nH]n3)c2)C(C)C1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-(3-dimethylaminopropenoyl)phenyl)-1-hexyl-3,4-dimethylpiperidine (Preparation 38, 117 mg, 0.32 mmol) in a mixture of methanol (5.0 mL) and water (1.0 mL) was added hydrazine hydrate (0.1 mL, 3.2 mmol). The mixture was heated at reflux for 2 h and then cooled to room temperature. The mixture was concentrated in vacuo and saturated aqueous sodium hydrogencarbonate (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL), the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane:0.88 ammonia (90:10:1). The title compound was isolated as clear oil (85 mg, 79%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC1CCN(Cc2ccccc2)C1=O
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCN(Cc2ccccc2)C1=Nc1ccccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 1, 1-benzyl-3-methyl-2-pyrrolidone (14.17 g) in benzene (80 ml) was reacted with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml) for 24 hours at 70° C. to give 4-[2-(1-benzyl-3-methyl-2-pyrrolidinylideneamino)phenyl]morpholine (m.p. 96°-97° C.) which was recrystallised from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:11][C:12]1[C:13]([F:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([F:22])=[C:14]([S:18]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1cccc(Cl)c1F
Yield: 61.6 %

Procedure:
Following General Procedure B, the title compound (386 mg, 62%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (297 mg, 1.71 mmol) and 3-chloro-2-fluoro-benzenesulfonyl chloride (392 mg, 1.71 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24]C4N(N=C(C5N(CC(F)(F)F)N=CN=5)C=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2OCC[C:48]3[C:44](=[N:45][N:46]([C:52]4[N:53]([C:57]5[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=5[F:64])[N:54]=[CH:55][N:56]=4)[CH:47]=3)C=2C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][C:48]4[C:44](=[N:45][N:46]([C:52]5[N:53]([C:57]6[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=6[F:64])[N:54]=[CH:55][N:56]=5)[CH:47]=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(Br)ccc2OCC3)c(F)c1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Yield: 77 %

Procedure:
4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared similarly to 4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from 9-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.55 mg, 1.13 mmol) to give the title compound as a colourless gum (1.47 g, 77%). LCMS RT=5.01 min, M+H+=547
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])(=O)C.[Na+].[S:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>C(O)C>[C:6]1([C:4](=[O:5])[CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][S:17][CH2:18]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(CCCl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CCN1CCSC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A solution containing 8.43 g (0.05 mol) of β-chloropropiophenone, 4.10 g (0.05 mol) of anhydrous sodium acetate and 4.01 g (0.045 mol) of thiazolidine in 30 ml of ethanol is stirred at 25° C. for 8 hours. After filtering off the precipitate and evaporating the solvent from the solution, the oily yellowish residue weighing 9.3 g is converted to the hydrochloride in a mixture of acetone and ether in the usual way to give 9.9 g of product. After recrystallization from methanol, the hydrochloride of the title product thus obtained melts at 170°-171° C.; it is identical to the hydrochloride described in Examples 1 and 43.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[CH:21][CH:20]=[N:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nccnc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4nccnc4c3O2)C1
Temperature: 80 °C

Procedure:
To a solution of (2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.856 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.639 g, 3.222 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.248 g (77%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.36 (silica, methanol:ethyl acetate 1:9); mp >220° C. dec.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH:15]2[O:30][C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([F:27])[C:26]=4[C:17]=3[CH2:16]2)[O:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[F:27][C:25]1[C:26]2[C:17]3[CH2:16][CH:15]([CH2:14][C@H:11]4[O:10][CH2:9][C@H:8]([NH:7][C:6]([C:40]5[CH:41]=[CH:42][C:36]6[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=6[CH:39]=5)=[O:5])[CH2:13][CH2:12]4)[O:30][C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][C:24]=1[O:28][CH3:29]
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2c1F)CC(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Product: COc1ccc2ncc3c(c2c1F)CC(C[C@@H]1CC[C@@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CO1)O3

Procedure:
The titled compound is prepared as an off-white lyophilized powder following Scheme 3 and in analogy to Example 13 using (3R,6S)-[6-(9-fluoro-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-ylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.CO.C(=O)(O)[O-].[Na+]>CO.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Combine 1-ethoxycarbonyl[1,4]diazepane (18.0 g, 104 mmol) and 2-chlorobenzimidazole (7.93 g, 52 mmol). Heat to 130° C. After 4 hours, cool to ambient temperature and add hot methanol to dissolve the reaction mixture. Add a saturated aqueous solution of sodium bicarbonate (150 mL) and concentrate in vacuo to remove most of the methanol. Combine the aqueous reaction mixture and 95/5 diethyl ether/ethyl acetate. Separate the aqueous layer and extract three times with dichloromethane. Combine the dichloromethane layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with ethyl acetate (100 mL) to give a solid. Chromatograph on silica gel eluting with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Triturate that residue with 9/1 diethyl ether/ethyl acetate to give a solid. Collect solid by filtration and dry in vacuo to give 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp; 161-162° C.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(C)(C)C.[NH2:16][C:17]1[C:22]([C:23]([C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[O:24])=[CH:21][N:20]=C(S(CC)(=O)=O)[N:18]=1>>[NH2:18][C:17]1[C:22]([C:23]([C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[O:24])=[CH:21][N:20]=[C:6]([NH:7][C@H:8]2[CH2:9][CH2:10][C@H:11]([NH2:14])[CH2:12][CH2:13]2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N

Procedure:
The title compound was prepared as in Example 113 and Example 114 using (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (Altech) and (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone Example 103. MS (M+H)+=378.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:5]2[C:6]([C:9](O)=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1.C[CH2:16][N:17]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.CN.Cl>CN(C=O)C>[NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:5]2[C:6]([C:9]([NH:17][CH3:16])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc2occ(C(=O)O)c2cc1Br
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1coc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, 199 mmol) in dry DMF (500 mL) was added EDCI (53.1 g, 298.77 mmol) and HOBT (40.4 g, 299 mmol). The reaction mixture was stirred at room temperature for 2 h, and then Et3N (60.5 g, 598 mmol) and MeNH2.HCl (40.3 g, 598 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and then 300 mL Na2CO3 (sat., a.q.) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (DCM:MeOH=30:1) to give the product 6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (38 g, yield: 71%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.19˜8.21 (m, 2H), 7.98 (s, 1H), 6.97 (s, 1H), 5.46 (br s, 2H), 2.75 (d, J=4.4 Hz, 3H). MS (M+H)+: 269/271.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]1)=[O:7].O[N:28]=[C:29]([NH2:31])[CH3:30]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH2:11][CH:10]([C:24]2[O:25][N:31]=[C:29]([CH3:30])[N:28]=2)[CH2:9]1)=[O:7]
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: CC(N)=NO
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C)no2)C1
Yield: 42.9 %

Procedure:
100 mg (0.26 mmol) of the compound from Example 105A and 40 mg (0.534 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Diastereomer separation of 62 mg of the cis/trans isomer mixture according to Method 12C gave 46 mg of the title compound and 5.7 mg of the trans isomer.