Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:6]2=[C:5]([C:19]([N:21]2C=CN=C2)=[O:20])[C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)#[N:2].N>O>[C:19]([C:5]1[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:3]([C:1]#[N:2])[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:6]=12)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1CCn2c(C#N)c(-c3cccc(F)c3)c(C(=O)n3ccnc3)c2C1
Agent: N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(C#N)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To 1.35 g (3.10 mmol) of tert-butyl 6-cyano-7-(3-fluorophenyl)-8-(1H-imidazol-1-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in an autoclave are added 10 ml of 30% aqueous ammonia. The mixture is stirred for 1 hour at 50° C. and, after cooling, is poured into 60 ml of water, to give 1.05 g of tert-butyl 8-carbamoyl-6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate after drying over potassium hydroxide.
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]4[C:24]([CH:27]=O)=[CH:25][CH:26]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2].Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]4[C:24](/[CH:27]=[N:34]\[OH:35])=[CH:25][CH:26]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2]
Reactant: NO
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C=O)ccc23)cc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(/C=N\O)ccc23)cc1OC
Temperature: 70 °C
Yield: 86 %

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (950 mg, 2.21 mmol) in ethanol (4.7 mL) was heated at 60° C. A solution of hydroxylamine hydrochloride (693 mg, 9.97 mmol) and sodium acetate (1.38 g, 16.8 mmol) in water (4.7 mL) was added to the carbaldehyde solution. The reaction mixture was heated at 70° C. for 30 minutes before it was cooled to room temperature. Water was added and the product formed a white precipitate which was collected by filtration. The solids were washed with water and toluene, and dried under reduced pressure to give (Z)-1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde oxime (847 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].Cl.CO[C:32]1C=C(C2C(C)(CCC)C(=O)N(C3CCNCC3)N=2)C=C[C:37]=1OC.ClCC(OC(=O)CCl)=O>>[Cl:1][CH2:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH2:17][CH2:32][CH3:37])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Reactant: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Agent: Cl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for A1 using 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4-propyl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B8) and chloroacetic anhydride as starting compounds.
Reaction SMILES: FS([O-])(=O)=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][NH+:14]=[C:15]2SC)=[CH:10][CH:9]=1.[NH3:20]>C(O)C>[NH2:20][C:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=2)[CH2:12][CH2:13][N:14]=1
Reactant: N
Reactant: COc1ccc2c(c1)C(SC)=[NH+]CC2
Agent: O=S(=O)([O-])F
Solvent: CCO
Product: COc1ccc2c(c1)C(N)=NCC2
Yield: 72 %

Procedure:
3,4-Dihydro-7-methoxy-1-methylthioisoquinolinium fluorosulfonate (10.0 g., 0.0362 mole) was added to ethanol (100 ml.) which was saturated with ammonia in a steel bomb. The stirred mixture was heated on a steam bath for 2 hours. The mixture was combined with material from four similar runs andd flash evaporated to dryness. The residue was partitioned between 5N NaOH (300 ml.) and methylene chloride. The organic layer was washed with water (2×) and dried with sodium sulfate. The solid obtained after removal of the methylene chloride was recrystallized from benzene to give 23 g. (72% yield) of 1-amino-3,4-dihydro-7-methoxyisoquinoline, m.p. 114°-117.5°. Recrystallization from ethyl acetate afforded the analytical sample, m.p. 117.5°-119.5°.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]([OH:26])=O)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH:44][C:24]([C:19]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 85.7 %

Procedure:
Prepared in the same manner as described for example 1. A solution of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.38 g, 1.04 mmol, 1 eq.) in anhydrous THF was treated with 1,1′-carbonyldiimidazole (0.17 g, 1.06 mmol, 1.02 eq.) and warmed as described. The reaction was allowed to cool and then treated with 3-(dimethylamino)propylamine (0.13 g, 1.25 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give a yellow oil. The oil was purified by silica gel flash chromatography using 10% 2M NH3 in methanol in diethyl ether as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (3-dimethylamino-propyl)-amide (0.40 g, 85% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][NH:14]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N+](C1C=C(C=CC=1)N)([O-])=O.[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36](Cl)(=[O:38])=[O:37])=[C:34]([CH3:35])[C:30]=2[CH:29]=1>>[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36]([N:14]3[C:15]4[C:11](=[CH:10][CH:9]=[C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:16]=4)[CH2:12][CH2:13]3)(=[O:37])=[O:38])=[C:34]([CH3:35])[C:30]=2[CH:29]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CN1CCN(c2ccc3c(c2)NCC3)CC1
Agent: Nc1cccc([N+](=O)[O-])c1
Product: Cc1c(S(=O)(=O)N2CCc3ccc(N4CCN(C)CC4)cc32)sc2ccc(Cl)cc12

Procedure:
The title compound (E123) was prepared from 6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole (prepared from 3-nitroaniline, using methodology of WO95/06637 Intermediate 3) (39 mg, 0.18 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (50 mg; 0.18 mmol) using the method of Example 1 (75 mg, 84%) MH+=462/464.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[CH3:37]>>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:24][CH2:25][N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]4[CH3:37])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2ccccc2c(=O)n1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K2CO3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) in acetronitrile (300 ml) was heated at reflux for 16 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2, 75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm. Recrystallization from ethanol yielded white crystals, 3.94 gm (53%), m.p. 164°-165° C. This material appeared pure by TLC over silica gel plates.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.C([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(N2CCNCC2)nc1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.17 mmol) was used in general procedure 3 with Boc-piperazine (0.868 mmol). The product was deprotected by treatment with TFA and purified by RP-HPLC to give N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(piperazin-1-yl)nicotinamide. MS (Q1) 554.0 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:40]CC1.[OH-].[Na+].OO.OC1CCNCC1>COCCOCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:12]([OH:40])[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Reactant: C1CCOC1
Agent: B
Agent: OC1CCNCC1
Agent: OO
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.05 g, 2.21 mmol) was partially dissolved in dry diethyleneglycol dimethyl ether (25 mL) and a solution of borane/THF complex (1M in THF, 13.2 mL, 13.2 mmol) was added dropwise. After stirring briefly at room temperature, the mixture was allowed to stand for 16 h. The mixture was then cooled in ice, and water (2 mL), 2M sodium hydroxide (6.5 mL) and 35% hydrogen peroxide (1.7 mL, 16.24 mmol) were added dropwise in sequence. The mixture was heated at 50° C. for 6 h, then cooled, diluted with water (approx. 45 mL) and extracted three times with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-8.5% methanol in DCM) to give the crude product (0.78 g, 71%), containing approx. 20% of 4-hydroxypiperidine isomer which was recrystallised twice from ethyl acetate/methanol to give racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester containing <5% of the cis isomer (0.38 g). LCMS RT=4.44, [M+H]+=495. 1H NMR 400 MHz (DMSO-d6) δ: 8.39 (1 H, d, J=8.25 Hz), 7.89 (1 H, s), 7.47 (1 H, d, J=2.62 Hz), 7.03 (1 H, dd, J=8.29, 1.80 Hz), 6.77 (1 H, s), 6.07-5.99 (1 H, m), 4.37-4.37 (6 H, m), 4.19-4.18 (1 H, m), 3.73-3.73 (1 H, m), 2.66-2.66 (3 H, m), 1.81-1.81 (1 H, m), 1.61 (6 H, d, J=6.01 Hz), 1.50 (9 H, s)
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][C:8]([O-:11])(C)[CH3:9].[K+].[CH3:13][C:14]1([CH3:28])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=C(C=O)[CH:17]=[CH:16][C:15]1=2>CS(C)=O.O1CCCC1>[CH3:13][C:14]1([CH3:28])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:7]([CH:8]3[CH2:9][O:11]3)[CH:17]=[CH:16][C:15]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C3CO3)ccc21
Reaction time: 0.5 h

Procedure:
33 g (0.15 mole) of trimethylsulfoxonium iodide were added at room temperature to a solution of 17 g (0.15 mole) of potassium tert-butylate in 150 ml of dried dimethyl sulfoxide. The mixture was stirred for 0.5 hour, after which a solution of 32.5 g (0.15 mole) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaldehyde in 100 ml of tetrahydrofuran was added dropwise. Stirring was continued for 1 hour, after which the mixture was poured onto water and extracted with ether. The organic phase was washed with water, dried over magnesium sulfate and evaporated down. 31.3 g of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-oxirane remained. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: Cl.Cl.[C:3]1([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].[C:25]([O:29][C:30]([N:32]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][C@H:33]1[C@H:39]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([F:50])[CH:44]=1)[C:40]([O-])=[O:41])=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C@@H:39]([C@H:33]2[N:32]([C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34]2)[C:40](=[O:41])[N:21]2[CH2:20][CH2:19][N:18]([C:10]3[C:9]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:14][N:13]=[C:12]4[NH:15][CH:16]=[CH:17][C:11]=34)[CH2:23][CH2:22]2)=[CH:44][C:45]=1[F:50]
Reactant: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)[O-])c2ccc(Cl)c(F)c2)CCC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2CCN(c3c(-c4ccccc4)cnc4[nH]ccc34)CC2)c2ccc(Cl)c(F)c2)CCC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.0200 g, 0.0570 mmol, see Example 19), (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-3-fluorophenyl)acetic acid (0.020 g, 0.0518 mmol, see Example D) and TBTU (0.0200 g, 0.0622 mmol) in DCM (1 mL) were added to DIEA (0.0361 mL, 0.207 mmol) and stirred at room temperature for 1 hour. The mixture was directly loaded to column and purified by chromatography (1:1 hexane:ethyl acetate) to give (S)-tert-butyl 5-((S)-1-(4-chloro-3-fluorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)ethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid. The solid was dissolved in DCM (1 mL) and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The resulting residue was dissolved in DCM (0.5 mL), and 2M HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (S)-2-(4-chloro-3-fluorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.009 g, 28%). MS APCI (+) m/z 546 detected.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.C(OC([N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]3[CH:31]=[N:32][N:33]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:34]=3)=[CH:27][CH:28]=2)[C:23]([NH2:42])=[N:22]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>ClCCl.CN(C)C=O.O1CCCC1>[CH2:35]([N:33]1[CH:34]=[C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[NH:21][N:22]=[C:23]3[NH:42][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH:31]=[N:32]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cnn(Cc4ccccc4)c3)ccc21
Reactant: CN(C)CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1n[nH]c2ccc(-c3cnn(Cc4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(dimethylamino)acetic acid (32 mg, 0.308 mmol) and oxalyl chloride (0.31 mL, 0.61 mmol) in dichloromethane (5 mL) and dimethylformamide (2 drops) was stirred at ambient temperature for about 1 hour then concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (3 mL) and added to a suspension of Example 303A (40 mg, 0.103 mmol) and potassium carbonate (43 mg, 0.308 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at ambient temperature for about 30 minutes then trifluoroacetic acid (4 mL) was added and the reaction mixture was heated at about 60° C. for about 20 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure, diluted with dichloromethane (20 mL) and washed with 15% aqueous sodium hydroxide solution (20 mL). The organic extract was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.32-7.40 (m, 2H), 7.25-7.32 (m, 3H), 5.35 (s, 2H), 3.16 (s, 2H), 2.33 (s, 6H), 1.91 (s, 3H). MS (ESI+) m/z 375 (M+H)+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([SH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O>CC(O)C>[CH:27]1([S:33][C:2]2[O:3][C:4]([C:7]3[N:12]=[C:11]([NH:13][C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=4)[CH:10]=[CH:9][CH:8]=3)=[CH:5][N:6]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: SC1CCCCC1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccnc(Nc2cccc(-c3cnc(SC4CCCCC4)o3)n2)c1
Yield: 70.6 %

Procedure:
A mixture of [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (50 mg, 0.174 mmol), K2CO3 (72 mg, 0.523 mmol) and cyclohexanethiol (64 μl, 0.523 mmol) in iPrOH (5 ml) were heated to reflux for 18 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure to a yellow gum. The gum was taken up in a minimum of DCM and precipitated with n-pentane to afford the title compound as a beige solid (45 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.10 (s, 1H), 7.56-7.78 (m, 4H), 7.17 (d, J=5.9 Hz, 1H), 6.75 (s, 1H), 3.71 (m, 1H), 2.31 (s, 3H), 2.08 (m, 2H), 1.64 (m, 8H). (ESI+) m/z 367 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:21][CH2:22][C:23](OC)(OC)OC>>[Cl:21][CH2:22][C:23]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Reactant: COC(CCl)(OC)OC
Product: O=c1[nH]c(CCl)nc2cc(-c3ncccc3C(F)(F)F)ccc12

Procedure:
Heat a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (100 mg, 0.356 mmol) in 2-chloro-1,1,1-trimethoxyethane (bp 138° C.) at 130° C. for 4 hours. Concentrate the mixture under reduced pressure to give 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one as an oil which crystallizes on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[NH:8][CH:7]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: Clc1ccc2c(c1)N=C(c1ccncc1)c1cc(Cl)ccc1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Clc1ccc2c(c1)NC(c1ccncc1)c1cc(Cl)ccc1O2

Procedure:
A 20.0 g. portion of 2,8-dichloro-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine (Example 2), 10.0 g. of lithium aluminum hydride and 800 ml. of ether are reacted as described in Example 3, giving 2,8-dichloro-10,11-dihydro-11-(4-pyridyl)dibenz[b,f][1,4]oxazepine, mp. 202°-205° C.
Reaction SMILES: [CH2:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH2:4][NH:3][CH2:2]1.Cl.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)=O>[N+:18]([C:17]1[C:12]([N:3]2[CH2:2][CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4]2)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(O)C1=CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=C(O)C1=CCN(c2ncccc2[N+](=O)[O-])CC1
Yield: 43.8 %

Procedure:
A well homogenised mixture of isoguvacine hydrochloride (497 mg, 3.04 mmol), 2-chloro-3-nitro-pyridine (482 mg, 3.04 mmol) and potassium carbonate (882 mg, 6.38 mmol), was stirred at 60° C. for 1.5 h. The reaction mixture was cooled, poured into a solution of water and formic acid (pH=3) and extracted with dichloromethane. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether-Acetic Acid 20:80:0.05) affording the title product (332 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[C@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]COCCO.C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CO>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[C@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13]
Reactant: COCCOCCOCCO
Reactant: COCCOCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COCCOCCOCCOCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C

Procedure:
Compound 2b was prepared using the same procedure as described for the synthesis of 2a with the following reactants and solvents: 2-(2-(2-methoxyethoxy)ethoxy)ethanol (1.32 g, 8 mmol), 4-N,N′-(dimethyl)aminopyridine (100 mg, 0.81 mmol), N-Boc-(L)-Alanine (1.51 g, 8 mmol) and DCC (1.67 g, 8.1 mmol) in dichloromethane (25 mL). Column chromatography (SiO2, 0.060-0.200 mm/1% MeOH in CH2Cl2) yielded compound 2b as a colorless to pale yellow oil (2.35 g, 7.1 mmol, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3cccc(F)c3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(CN2CCN(c3cccc(F)c3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(m-fluorophenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(m-fluorophenyl)-4-[(4-aminophenyl)methyl]piperazine.