Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:13][Br:12])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NNC(=O)c1ccc(CBr)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottom flask was added 2.1 g (12.3 mmol) of 4-chlorobenzoic acid hydrazide, 3.20 g (12.3 mmol) of 4-bromomethyl-3-nitro benzoic acid, 3.54 g (18.5 mmol) of EDC, and 200 mL of DCM. Allowed to stir at room temperature for 18 h. Removed ⅔ of DCM, added water and filtered off white solid and washed with Et2O to give 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 1 H) 5.12 (s, 1 H) 7.59-7.64 (m, 2 H) 7.91-7.95 (m, 2 H) 7.96 (d, J=8.21 Hz, 1 H) 8.22-8.29 (m,1 H) 8.57 (dd, J=6.57, 1.77 Hz, 1 H) 10.76 (s, 1 H) 10.94 (dd, J=5.18, 0.88 Hz, 1 H). MS (m/z) 413.9 M (+1), tR=1.28, Meth 10. To a 500 mL round-bottom flask was added 4.95 g (12.0 mmol) of 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide, 6.09 g (36.0 mmol) DMC, and 100 mL of DCE. To this pale yellow solution was added 6.70 mL (48.0 mmol) of Et3N, slowly over 5 min. The dark green solution was allowed to stir at 40° C. for 30 min. then cooled to room temperature stirred for 18 h. Removed solvent and purified over a silica plug 10-30% EtOAc/Hep to give the title compound as yellow solid. MS (m/z) 350.0 M (+1), retention time=1.51, Method 10.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[S:28][CH:29]=[CH:30][N:31]=1)CCC>>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:4]1[C:5]2[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=2[C:2]([C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[CH:3]1)#[N:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccc3C#N)c2C1
Product: CC1(C)CC(=O)c2c(-c3nccs3)cn(-c3ccccc3C#N)c2C1
Yield: 44 %

Procedure:
In the same way as described in Example 15, Step 4 using 3-bromo-1-(2-cyanophenyl)-6,6-dimethyl-4,5,6,7-tetrahydroindol-4-one and 2-tributylstannylthiazole, the title compound (200 mg, 44%) was isolated as a colourless solid. 1H NMR (400 MHz, d6-DMSO) δ 1.05 (6H,s), 2.43 (2H,s), 2.53 (2H,s), 7.63 (1H,d, J=3.3 Hz), 7.75-7.80 (4H,m), 7.92 (1H,dd, J=7.8 and 1.4 Hz), 8.13 (1H,dd, J=7.7 and 1.3 Hz). MS (ES+) 348 (M+1).
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[CH3:14][N:15]([C:11]([CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:13])[C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1CCCc2ccccc21)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 417.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[Si:21]([C:25]#[CH:26])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:19]=[C:18]([C:26]#[C:25][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(N)=O)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)cc1=O
Yield: 100 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow solid (100%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 10.66 (s, 1H), 8.38 (s, 1H), 7.92 (br s, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.48 (br s, 1H), 7.42 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 5.73 (s, 1H), 3.38 (s, 3H), 0.23 (s, 9H). HRMS (EI+) calcd C18H20FN3O2Si (M+) 357.1309, found 357.1308.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.Br[CH:18]([CH3:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[S:15][C:18]([CH3:27])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:16]=3)=[CH:11][CH:12]=2)[CH:6]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccccc4)c(C)s3)cc2)cn1
Yield: 94 %

Procedure:
Prepared in analogy to example 64d) from 100 mg (0.43 mmol) [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and 101 mg (0.47 mmol) 2-bromopropiophenone. 140 mg (94%) of the product was isolated as a colorless solid. MS ISP (m/e): 347.1 (100) (M+H)+. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.48 (s, 1H), 9.46 (s, 1H), 7.93 (s, 1H), 7.88 (d, 2H), 7.69 (d, 2H), 7.47 (t, 2H), 7.36 (t, 1H), 2.46 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: C(OC(=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)[CH3:8])(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:25]1[CH:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:8])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:28]=[CH:27][N:26]=1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccnc(F)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3ccnc(F)c3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(2-fluoro-pyridin-4-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(2-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 52%.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[N:22])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.N.[OH:24]O>C(O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]([NH2:22])=[O:24])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: OO
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C#N)c2c(N)ncnn12
Agent: N
Solvent: CCO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C(N)=O)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
to a solution of Compound 14 (12 mg) in ethanol (4.8 mL) was added 0.7 mL 28% aqueous ammonia and 0.18 mL 30% hydrogen peroxide. The mixture was stirred in a sealed vial at RT for 19 h. The solvent was removed in vacuo, and the crude product was purified on flash silica gel eluting with 10% MeOH in EtOAc to afford the product as pale yellow solid (9.1 mg). This material was recrystallised from EtOAc/MeOH to afford Compound 15 (6.5 mg) as a colourless solid: ESI-MS m/z 324 ([M+H]+); 1H NMR (500 MHz, d6-DMSO): δ 10.38 (d, J 3.1 Hz, 1H), 8.07 (br s, 1H), 8.04 (d, J 3.1 Hz, 1H), 7.91 (s, 1H), 7.52 (br s, 1H), 7.23 (s, 1H), 5.39 (s, 1H), 4.98 (d, J 7.4 Hz, 1H), 4.74 (s, 1H), 4.64 (t, J 5.8 Hz, 1H), 3.82-3.73 (m, 2H), 3.71-3.66 (m, 1H), 3.55 (dd, J 7.1 Hz, 8.3 Hz, 1H), 0.82 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]OS(C)(=O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][NH2:23]>>[CH:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8][NH:23][CH3:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCC1
Product: CNC[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Yield: 43 %

Procedure:
A mixture of crude tert-butyl (S)-3-cyclopentyl-1-(methanesulfonyloxy)propan-2-ylcarbamate in ethanolic methylamine (30 mL) was heated under reflux overnight. The solvent was removed in vacuo and the residue was purified by silica chromatography to obtain tert-butyl (S)-3-cyclopentyl-1-(methylamino)propan-2-ylcarbamate (900 mg, 43% for 3 steps from) as a solid (900 mg, yield 43% for 3 steps from tert-butyl (S)-3-cyclopentyl-1-(t-butyldimethylsilyloxy)propan-2-ylcarbamate). 1H NMR (CDCl3, 400 MHz) δ 1.10 (m, 2H), 1.44 (s, 9H), 1.49 (m, 3H), 1.60 (m, 3H), 1.81 (m, 3H), 2.69 (s, 3H), 2.90 (m, 1H), 3.17 (m, 1H), 3.92 (brs, 1H), 5.66 (brs, 1H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH2:20][CH2:21][CH3:22])=[C:9]([CH:17]=[CH:18][CH:19]=1)[C:10]([O:12]C(C)(C)C)=[O:11].O>C1(C)C=CC=CC=1>[OH:6][C:7]1[C:8]([CH2:20][CH2:21][CH3:22])=[C:9]([CH:17]=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11]
Reactant: CCCc1c(OC)cccc1C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(O)cccc1C(=O)O
Temperature: -25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Add boron tribromide (305.6 mL, 305.6 mmol) dropwise while maintaining the temperature below 0° C. to a solution of tert-butyl 3-methoxy-2-propyl-benzoate (61.2 g, 244 mmol) in toluene (428 mL) which has been cooled to −25° C. Stir at −5° C. for 3 h. Add water (100 mL) dropwise, raising the temperature to 7° C., and stir 30 min. Concentrate the mixture in vacuo and then suspend the semisolid in water (200 mL). Stir 1 h and filter the suspension through a glass frit. Wash the collected solid with water and dry the solid to yield the title compound (43.1 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.0 Hz, 1H); 7.16 (t, J=8.0 Hz, 1H); 6.99 (d, J=7.7 Hz, 1H); 5.0 (bs, 2H); 2.98 (t, J=7.7 Hz, 2H), 1.64 (m, 2H); 1.02 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[CH3:38])[C:32](O)=[O:33]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([CH3:38])=[C:29]([CH3:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: Cc1ccc(C(=O)O)cc1C
Agent: Cl
Product: Cc1ccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)cc1C

Procedure:
Compound 58d was reacted with 3,4-dimethylbenzoic acid and subsequently hydrogenated according to the the procedure described in Example 58, to give Example 61. ESI-MS m/e 355.5 (M+1).
Reaction SMILES: [F:1][C:2]([F:29])([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C>C1COCC1>[F:29][C:2]([F:1])([CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][CH:10]([OH:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(3aR,4R,5R,6aS)-4-(3,3-Difluoro-4-phenoxybutyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one, prepared in Step E, was dissolved in anhydrous THF (0.5 M) under nitrogen atmosphere and cooled to −78° C. A solution consisting of DIBAL-H (2 molar equivalents, 1 M in toluene) is added to the reaction mixture dropwise and stirred for 3 hours. Ethyl acetate (20 mL) is added and the mixture is stirred for an additional 5 minutes. The mixture is subsequently treated with 30% aqueous K, Na tartrate and stirred vigorously overnight. The layers are separated and the organic phase is filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes to afford the title intermediate.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[CH3:13][C:14]([S@@:17](/[N:19]=[CH:20]/[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:18])([CH3:16])[CH3:15]>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:20]([C:21]2[C:26]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:19][S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ncccc2C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
Magnesium metal (0.095 g, 3.91 mmol) was activated using a crystal of iodine prior to addition of THF (1 mL). 1-Bromo-4-methoxybenzene (0.400 g, 2.139 mmol) was added, and the reaction was left without stirring for 5 minutes after which initiation was observed. Additional THF (15 mL) was added, and the resulting mixture was stirred for 2 hours. Next, (S,E)-2-methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide (0.500 g, 1.797 mmol) was added, and the mixture was stirred for 10 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (150 mL) were added, and the phases were mixed and separated. The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave (S)—N—((S)-(4-methoxyphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C=O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][C:23](=[O:24])[O:25][CH2:26][CH3:27])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCC(C)Sc1ccc(OCCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(SC(C)CC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of the above amine (2.41 g, 10.0 mmol) in 10 ml DMF, cooled to 0° and under N2, is added potassium carbonate (1.66 g, 12.0 mmol) followed by dropwise addition of ethyl chloroformate (1.2 ml, 12.0 mmol) in 5 ml of DMF. After 1.5 hours, water is added and the aqueous phase is extracted with ether. The combined organic layers are washed with water and brine, dried, rotoevaporated and the residue is purified by column chromatography to give ethyl N-{2-[4-(1-methylpropylthio)phenoxy]ethyl}carbamate (compound 40, Table A).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC(C)C)cn1
Yield: 82 %

Procedure:
As described for example 162b, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) was converted using isopropylamine instead of ethanolamine to the title compound (SiO2, heptane:ethyl acetate=50:50 to 0:100, 185 mg, 82%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]([O:17]C)=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]([OH:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COc1cc(OC)c(NC(=O)c2ccccc2)cc1Cl
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)c(O)cc1O)c1ccccc1

Procedure:
To a stirred solution of N-(5-chloro-2,4-dimethoxyphenyl)benzamide (292 mg, 1 mmol) in DCM (10 mL) 1M boron tribromide in DCM (3 mL, 3 mmol) was added dropwise at ambient temperature. A precipitate was formed after 30 min. The stirring was continued over night. The mixture was quenched with methanol (5 mL) and concentrated in vacuo leaving an oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=2)O)[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([Cl:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C(O)c2cccc(Br)n2)n1
Solvent: ClCCl
Product: COc1cccc(C(Cl)c2cccc(Br)n2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (6-bromopyridin-2-yl)(6-methoxypyridin-2-yl)methanol (5.11 g, 17.31 mmol) in CH2Cl2 (56 mL) @ 0° C. under N2 was added SOCl2 (3.09 g, 25.97 mmol). The mixture was then allowed to warm to rt and stirred for 3 hr. The mixture was then cooled back to 0° C. and quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted 3× with CH2Cl2. The combined organics were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (25-35% CH2Cl2 in Hexanes) to give 2-bromo-6-[chloro(6-methoxypyridin-2-yl)methyl]pyridine. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, 1H, J=7.8), 7.61-7.54 (m, 2H), 7.41 (d, 1H, J=7.8), 7.12 (d, 1H, J=7.1), 6.66 (d, 1H, J=8.3), 6.02 (s, 1H), 3.86 (s, 3H), LRMS m/z (M+H) Calcd.: 313.0, found: 312.9.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])C.[CH:18]1[CH:29]=[C:28]2[C:21]([C:22]([CH:24]=[CH:25][C:26]2=[O:27])=[O:23])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:6]([C:5]2[C:24]3[CH:25]=[C:26]([OH:27])[C:28]4[C:21](=[CH:20][CH:19]=[CH:18][CH:29]=4)[C:22]=3[O:23][CH:4]=2)=[O:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2coc3c2cc(O)c2ccccc23)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
A suspension of enaminone 12 (2.0 g, 8.43 mmol) and NQ-1 (1.33 g, 8.43 mmol) in acetic acid (20 ml) was stirred at room temperature for 5 h under an atmosphere of N2. The resulting precipitate was filtered, washed with water, and dried under high vacuum to afford compound 24 (1.5 g, 50%) as an off-white solid. TLC Rf=0.5 (petroleum ether-EtOAc, 5:5); 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.70 (app t, 1H), 7.60-7.50 (band, 4H), 7.15 (d, J=8.3 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H); MS (ES) m/z 349 (M+H)+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]([NH2:27])[NH2:26])=[CH:20][CH:19]=1.C(O)(O)=O>CN1C(=O)CCC1.O>[C:21]1([NH:24][C:25]2[N:27]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:26]=2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Reactant: NC(N)=Nc1ccccc1
Agent: O=C(O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of (2E)-3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (0.49 g, 2 mmol) and phenylguanidine carbonate salt (0.30 g, 2.2 mmol) in NMP (4 ml), is stirred at 120° C. for 2 days. It is then cooled to room temperature and diluted with water (40 ml). The resulting suspension is filtered, and the precipitate is washed with 50% ammonium chloride solution, water, and hexanes, and then dried in vacuo to give 0.56 g of an off-white solid; mp 162-163° C.; HRMS: calcd for C17H12F3N3, 315.0983; found (ESI_FTMS, [M+H]1+), 316.1048.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:13]2[C:21]([Cl:22])=[C:20]([Cl:23])[C:19]([Cl:24])=[C:18]([Cl:25])[C:14]=2[C:15]([OH:17])=O)=[O:12])=[C:3]1[CH3:26].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C.[OH-].[NH4+]>Cl>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:11]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:26])[C:13]2[C:14](=[C:18]([Cl:25])[C:19]([Cl:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])[C:15](=[O:17])[O:12]1
Reactant: Cc1c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc2n1C
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc2n1C
Temperature: 25 °C

Procedure:
A mixture of 1.55 g (0.0036 mole) of 2-[(1,2-dimethyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid prepared in a manner similar to part A of Example 2, 0.58 g (0.0035 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and ten ml of acetic anhydride was heated to reflux for approximately one hour. After cooling to room temperature, the reaction mixture was poured into 20 ml of 10 percent hydrochloric acid and the mixture then rendered alkaline by the addition of concentrated ammonium hydroxide. The purple solid which separated was collected by filtration, dried, and recrystallized twice from isopropyl acetate to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1,2-dimethyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R°=R1 =R2 =R3 =Cl; R=R5 =R6 =CH3 ; R4 =N(CH3)2 ; Y1 =H) which decomposed at 228°-229° C. The mass spectrum showed an m/e at 575 (M+, 4 Cl). A toluene solution of the product spotted on silica gel developed an intense purple-colored image.