Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[N:26]=[CH:27][N:28]([CH2:30][CH2:31][CH2:32][OH:33])[CH:29]=1.CC([O-])(C)C.[K+]>COCCOC.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:32][CH2:31][CH2:30][N:28]4[CH:27]=[N:26][N:25]=[CH:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OCCCn1cnnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCn4cnnc4)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidin-1-carboxylic acid tert-butyl ester (31.6 mg, 95.5 μmol), as prepared in Example 65b, 3-[1,2,4]-triazol-4-yl-propan-1-ol (ChemPacific) (12.0 mg, 94.5 μmol), and KOtBu (11.7 mg, 104 μmol) in DME (100 μL) and DMSO (50 μL) was stirred at rt for 1 hr. The resulting homogeneous amber solution was partitioned with DCM (2 mL) and 0.5M sodium phosphate/pH 7 (2 mL). The organic layer was concentrated to provide the crude title compound that was used immediately for the next step. LC/MS (ESI): calcd mass 438.2, found 439.1 (MH)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([NH:17][CH2:18][CH:19]([CH2:23][NH:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH:20]([OH:22])[CH3:21])=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:28]([O:27][C:25]([NH:24][CH2:23][CH:19]([CH2:18][NH:17][C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C:20](=[O:22])[CH3:21])=[O:26])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
To a solution of 0.32 ml of oxalyl chloride in 10 ml of dichloromethane was added 0.54 ml of dimethyl sulfoxide at -78° C. under nitrogen. After stirring for 5 minutes, a solution of 1.00 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-ol in 2 ml of dichloromethane was added. After stirring for 30 minutes, 2.43 ml of triethylamine was added to the mixture and then the temperature of the mixture was raised to room temperature. The mixture was extracted with chloroform and the organic layer was washed in turn with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by a column chromatography on silica gel (hexane:ethyl acetate=1:1) gave 0.77 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-one.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12](F)[CH:11]=1)=[O:8])#[N:3].C(OC(N1CCO[C@@H](C2C=CC(N)=C([Cl:48])C=2)C1)=O)(C)(C)C>>[ClH:48].[Cl:1][C:11]1[CH:12]=[C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:4]([C:2]#[N:3])[CH:5]=1
Reactant: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(F)c2)cc(C#N)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2Cl)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methoxy-isonicotinic acid (described in example 107) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42]N(C)[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: NCCCCCCC(=O)O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCCCCC(=O)O)C1
Yield: 5 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 7-amino-heptanoic acid as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (11.2 mg, 5% yield). 1H NMR (500 MHz, CDCl3) δ: 11.95 (bs, 1H), 11.00 (s, 1H), 7.61 d, 1H, J=8.24), 7.52 (s, 1H), 7.25 (s, 1H), 4.58 (s, 2H), 4.04 (s, 2H), 3.36 (m, 2H), 2.98 (s, 3H), 2.18 (t, 2H, J=7.33), 1.48 (m, 4H), 1.26 (m, 4H). HRMS (M+H) calcd for C20H25N2Cl2O5: 443.1140. found: 443.1153.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(B(O)O)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Temperature: 80 °C
Yield: 77.9 %

Procedure:
A flask was charged with 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.13 g, 0.36 mmol) (as prepared in the previous step), cyclohex-1-enyl boronic acid (0.060 g, 0.48 mmol), Pd(PPh3)4 (0.04 g, 10 mol %), aqueous 2M Na2CO3 (1.5 mL), ethanol (1.5 mL), and toluene (3 mL), and heated at 80° C. for 3 h. The reaction was diluted EtOAc (10 mL), washed with NaHCO3 (2×10 mL) and brine (10 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.10 g (85%) of the title compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C22H32N2O2, 357.2 (M+H), found 357.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][C:5]([C:18](O)=[O:19])=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N:38]1[CH:42]=[CH:41]N=C1)(N1C=CN=C1)=O.[C:43]1(NCCCCCCCC)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[C:43]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:41][CH2:42][NH:38][C:18]([C:5]2[CH:4]=[C:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2]([NH2:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[CH:6]=2)=[O:19])[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Nc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)O)cc1-c1cccc(C(F)(F)F)c1
Reactant: CCCCCCCCNc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: Nc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.4 %

Procedure:
To a solution of 2′-amino-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-5′-carboxylic acid (0.113 g, 0.27 mmol 1 eq) in DMP (2.7 mL) was added 1,1′-carbonyldiimidazole (0.120 g, 0.74 mmol 2.7 eq) and phenyl octylamine (0.070 mL, 0.35 mmol, 1.3 eq) and the reaction was stirred overnight at rt. Additional 1,1′-carbonyldiidazole (0.124 g, 0.76 mmol 2.8 eq) and phenyl octylamine (0.070 mL, 0.35 mmol, 1.3 eq) was added and stirring was continued overnight. The solids were then filtered off and washed with EtOAc. The filtrate was washed with saturated NaHCO3 solution, 0.1 N HCl and brine. It was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc:Hexane+1% Formic acid) to afford the title compound (0.150 g, 37%) as a light yellow oil. 1H NMR (DMSO-d6 δ8.20 (t, 1H); 7.81-7.70 (m, 8H); 7.61 (s, 2H); 7.25-7.12 (m, 5H); 4.87 (s, 2H); 3.19 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.28 (m, 8H); IR (KBr) 3540, 3350, 2950, 2850, 1620, 1545, 1480, 1420, 1325, 1180, 1120, 1110, 1080 cm−1; mass spectrum [(+)APCI], m/z 613 (M+H)+; Anal. Calcd. for C35H34F6N2O: C, 68.62; H, 5.59; N, 4.57, Found: C, 67.66; H, 5.96; N, 4.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C[O:12][C:13](=[O:42])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:31]1[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=1[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:42])=[O:12])=[C:17]([CH3:41])[CH:18]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3Cl)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-chlorophenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 122 mg (66%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H22O4F3Cl 526, found 527 and 529 (M+1 and M+3,100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1.IC>CO>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: CI
Solvent: CO
Product: O=[N+]([O-])c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the 4-nitrobenzene-1,2-diamine in methanol was treated with 4-bromo phenyl isothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and purified on silica gel to yield (4-bromophenyl)(5-nitrobenzimidazol-2-yl)amine. The product was taken in methanol and hydrogenated with catalytic amount of 10% Pd/C to give ((5-aminobenzimidazol-2-yl)(4-bromophenylamine). MS: MH+=302.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]1>C(O)CCC>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[S:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[N:10]=[C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C@H:37]3[CH2:42][CH2:41][C@H:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]3)[N:7]=2)[CH:19]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Solvent: CCCCO
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2nccc(-c3sc(N4CCCC4)nc3-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3)n2)CC1
Temperature: 60 °C

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide was dissolved in n-butanol and N-(4-aminocyclohexyl)methanesulfonamide (27.0 mg, 0.140 mmol) was added at rt followed by TEA (52.2 μl, 0.375 mmol). The reaction was heated to 60° C. for 12 h. Purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions were combined and washed with NaHCO3, dried over MgSO4 and solvent removed to give the title compound as a yellow solid (0.010 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J=5.1 Hz, 1H), 7.38-7.55 (m, 1H), 7.11-7.31 (m, 2H), 6.93-7.10 (m, 3H), 6.72-6.88 (m, 1H), 6.42-6.48 (m, 1H), 6.28-6.35 (m, 1H), 5.79-5.88 (m, 1H), 3.52-3.63 (m, 1H), 3.29-3.45 (m, 6H), 3.05-3.16 (m, 1H), 2.91 (s, 3H), 1.77-2.02 (m, 6H), 1.19-1.42 (m, 4H). MS (ESI): 690 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH3:7])[N:6]=1.NC1N(C)N=NN=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O>C1(C)C=CC=CC=1>[CH3:7][N:5]1[N:4]=[N:3][C:2]([N:1]=[CH:20][C:19]2[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)=[N:6]1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cn1nnc(N)n1
Agent: Cn1nnnc1N
Solvent: Cc1ccccc1
Product: Cn1nnc(N=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
A crude mixture of 5-amino-2-methyltetrazole and 5-amino-1-methyltetrazole is treated with 3,5-bis(trifluoromethyl)benzaldehyde (48 mL, 71 g, 0.29 mol) in toluene (780 mL), and the mixture is stirred and refluxed for 5 hours. The resulting mixture is filtered to remove off the insoluble solid (5-amino-1-methyltetrazole), and the residue is washed with hot toluene. The filtrate is concentrated to give crude 2-methyl-N-[3,5-bis(trifluoromethyl)phenylmethylene]-2H-tetrazole-5-amine (70.1 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNC1CCCCC1.C(O)C>[CH:22]1([N:23]([CH3:26])[CH2:19][C@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:21][CH2:2][CH2:3][CH2:4]1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Solvent: CCO
Solvent: CNC1CCCCC1
Product: CN(C[C@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1)C1CCCCC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylcyclohexylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH:57]([CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH:58]([CH3:60])[CH3:59])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][N:62]2[CH2:61][CH:57]([CH:58]([CH3:59])[CH3:60])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:69][CH:68]=1
Reactant: CCOC(=O)C(CNCc1ccc(F)cc1)C(C)C
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.174 g, 0.492 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.206 g, 0.542 mmol) and 4-methylmorpholine (0.109 mL, 0.990 mmol) were added sequentially to a solution of rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (0.132 g, 0.494 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (10 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.28 mL, 3.96 mmol) was added and the reaction mixture was heated to 70° C. for 38 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-isopropyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.100 g, 0.180 mmol, 36%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.73 (3H, d, J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 1.86-1.94 (1H, m), 2.35 (1H, bs), 2.96 (3H, s), 3.33 (1H, dd, J1=3.5 Hz, J2=13.0 Hz), 3.55 (1H, dd, J1=5.6 Hz, J2=13.3 Hz), 4.24 (2H, d, J=6.3 Hz), 4.52 (1H, d, J=14.8 Hz), 4.68 (1H, d, J=14.6 Hz), 7.14-7.19 (2H, m), 7.25 (1H, s), 7.37-7.41 (2H, m), 7.64 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C22H25FN4O6S3 556.09. found 557.1 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.C(O)C.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[S:9][N:8]=[C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)[C:11]=2[CH:12]=1
Reactant: Cn1cccc1-c1nsc2ccc([N+](=O)[O-])cc12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cccc1-c1nsc2ccc(N)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a mixture of 3-(1-methylpyrrol-2-yl)-5-nitro-1,2-benzisothiazole(1.5 g, 5.79 mmol), ethyl acetate and ethanol is added tin(II) chloride dihydrate (6.5 g, 28.8 mmol). The resultant mixture is heated to reflux, stirred 30 min at reflux and cooled to room temperature. The mixture is diluted with ethyl acetate and slowly quenched with solid sodium bicarbonate and water. Brine is added and the resultant mixture stirred and allowed to stand until layer separation is complete. The organic layer is saved and the aqueous layer is extracted with ethyl acetate. The solids which form in the aqueous layer are triturated with ethyl acetate, filtered and the filtrate combined with the above organic layers. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a brown oil (1.10 g, 84.6%) identified by NMR spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=3)[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:31][O:30][C:26](=[O:29])/[CH:27]=[CH:28]/[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[O:15][C:11]1([CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH2:23][C:22]2=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of (±)-6-bromo-4-oxo-spiro(chromane-2,4′-azepane)-1′-carboxylic acid tert-butyl ester (7.20 g, 17.6 mmol), Pd(OAc)2 (78 mg, 0.35 mmol), P(o-tol)3 (213 mg, 0.70 mmol), TEA (7.32 ml, 52.7 mmol), methyl acrylate (4.74 ml, 52.7 mmol) in dry DMF (20 ml) was heated under N2 atmosphere to 100° C. for 3 h. After cooling down to RT, the solution was filtered on a celite pad and washed with EtOAc (100 ml). The filtrate was washed with water and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 8:2 to 7:3) to give (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (7.1 g) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]O>>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: OCCBr
Reactant: Oc1cccc(Cl)c1Cl
Product: Clc1cccc(OCCBr)c1Cl

Procedure:
This example was prepared by substituting 1-naphthol with 2,3-dichlorophenol and substituting 3-bromopropanol with 2-bromoethanol in EXAMPLE 31A.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([O:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)C1C=CC=CC=1.CN(C)C1C=CC=CC=1.Cl>ClCCl>[Br:20][C:15]1[CH:14]=[C:13]([OH:12])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Oc1cc(F)cc(Br)c1
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
Add aluminum chloride (13.51 g, 101.38 mmol) to 1-benzyloxy-3-bromo-5-fluoro-benzene (9.50 g, 33.79 mmol, prepared according to WO 03/101956) and dimethylaniline (40.96 g, 337.92 mmol) in dichloromethane (84 mL) at −0° C. under nitrogen and stir 10 minutes. Remove ice-bath and stir 2 hours. Add 60 mL 2N hydrochloric acid dropwise. Separate layers and wash the organic layer with 2N hydrochloric acid (4×50 mL). Extract the organic layer with 3N potassium hydroxide (4×50 mL). Acidify with 5N hydrochloric acid and extract with dichloromethane (3×50 mL). Dry the dichloromethane layer (sodium sulfate) and concentrate to give 4.3 g (66.6%) of the desired compound as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([SH:17])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br-].[CH2:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C)C=O.O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:17][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCCC1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(S)cc12
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(SC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
1-(1′-Acetyl-5-mercaptospiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (26 mg, 0.076 mmol) was dissolved in dimethylformamide (1 mL). Thereafter, potassium carbonate (32 mg, 0.23 mmol) and cyclopentane bromide (23 mg, 0.15 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous magnesium sulfate, followed by concentration in vacuo. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=20:1) to obtain 1-(1′-acetyl-5-(cyclopentylthio)spiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (13 mg, 42%) in the form of a colorless oily product.