Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=1.ClC1C=CC(N)=NC=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:41]5[CH:42]=[CH:43][CH:44]=[C:39]([F:38])[CH:40]=5)=[CH:27][C:26]=4[NH2:34])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: Nc1ccc(Cl)cn1
Product: Nc1cc(C(=O)Nc2cccc(F)c2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1

Procedure:
A mixture of the product from Example 19C was reacted with 3-Fluoro-phenylamine using the procedure of Example 19D substituting 3-Fluoro-phenylamine for 5-chloro-2-aminopyridine followed by reduction of the nitro group following the procedure of Example 19E to provide the title product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:38][S:39](O)(=[O:41])=[O:40]>C(OCC)(=O)C>[CH3:38][S:39]([O:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[C:12]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)[CH:17]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)O
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 1 h

Procedure:
Heat approximately 1.0 g of the compound of Example 3 in a solvent mixture consisting of 3 mL of 3A-ethanol and 5 mL ethyl acetate to provide a thin slurry. Add methanesulfonic acid (185 mg) in 1 mL of 3A-ethanol to the hot slurry. Cool and stir for approximately 1 hour upon reaching room temperature. Filter the slurry and rinse with ethyl acetate. Vacuum dry the filter cake at 45° C. over 2-3 days to recover approximately 1.11 g of the title compound.
Reaction SMILES: OC([C:4]([F:7])([F:6])[F:5])=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:46]([CH3:48])[CH3:47])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][C:33]=3[O:41]C(F)(F)F)=[CH:28][CH:27]=2)[N:25]=1)=[O:15])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:73]([O:77][C:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]2[CH:91]=[CH:90][C:89]([NH2:92])=[CH:88][N:87]=2)[C@H:82]([CH3:93])[CH2:81]1)=[O:79])([CH3:76])([CH3:75])[CH3:74].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:73]([O:77][C:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]2[CH:91]=[CH:90][C:89]([NH:92][C:38]([C:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:30]=[CH:31][C:26]([C:24]5[N:25]=[C:21]([C@@H:17]6[CH2:18][CH2:19][CH2:20][N:16]6[C:14](=[O:15])[C@@H:13]([NH:12][C:10]([O:9][CH3:8])=[O:11])[CH:46]([CH3:48])[CH3:47])[NH:22][CH:23]=5)=[CH:27][CH:28]=4)=[C:33]([O:41][C:4]([F:5])([F:6])[F:7])[CH:34]=3)=[O:39])=[CH:88][N:87]=2)[C@H:82]([CH3:93])[CH2:81]1)=[O:79])([CH3:76])([CH3:74])[CH3:75]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)O)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylic acid TFA (600 mg, 0.9 mmol) and HATU (364 mg, 0.96 mmol) in DMA (8 mL) was stirred at RT for 15 min and then 0.5 M (R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester in DMA (1.7 mL) was added followed by N,N-diisopropylethylamine (0.76 mL, 4.36 mmol). The resulting mixture was heated at 55° C. overnight, washed with EtOAc (100 mL) and water (25 mL). The organic layer was washed again with water and then with brine, dried over sodium sulfate, filtered, and concentrated to yield a dark reddish oil which was purified by silica gel chromatography (40 g silica column, 0-80% hexane:EtOAc) to provide (R)-4-{5-[(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-pyridin-2-yl}-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (646 mg) as a light brownish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)#[N:24]>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=452.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:7]=[C:6]([C:8](O)=[O:9])[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=1.[NH2:23][C:24]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:25]=1[C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].C(N(CC)CC)C>C(#N)C>[CH3:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:24]=1[NH:23][C:8]([C:6]1[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:7]=1)=[O:9]
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of the title compound of Example 3, Step B (0.54 g, 1.1 mmol), the title compound from Example 1, Step B (0.44 g, 2.4 mmol) and BOP chloride (bis(2-oxo-oxazolidinyl)phosphinyl chloride, 0.54 g, 2.1 mmol) in acetonitrile (13 mL) was treated with triethylamine (0.9 mL). The mixture was shaken in a closed scintillation vial for 18 h. The reaction was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid. The ethyl acetate layer was washed successively with 1N hydrochloric acid (50 mL), 1N sodium hydroxide (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The title compound (0.43 g), a compound of the present invention, was isolated as a white solid. m.p. 227-230° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([CH2:1][NH:22][CH3:21])[CH:4]=2)[N:14]=1
Reactant: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)n1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2nc(C)ccc2C#N)c1
Yield: 56.8 %

Procedure:
2-(3-Formyl-phenoxy)-6-methyl-nicotinonitrile (0.77 g, 3.2 mmol), methylamine (2M in methanol, 7.0 mL, 14 mmol) and sodium cyanoborohydride (250 mg, 4.0 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (100 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.36 g, 3.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 6-methyl-2-(3-methylaminomethyl-phenoxy)-nicotinonitrile fumarate (650 mg, 55%) as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[C:53]([F:56])([F:55])[F:54]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([C:53]([F:55])([F:56])[F:54])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(C(F)(F)F)ccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro-1-(trifluoromethyl)benzene and isolated as white solid. MS(m/e): 509.3 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=O.[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:23][CH2:22]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.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:24]2[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]2)=[CH:33][CH:32]=1)=[O:18]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(Cc2ccc(NC(=O)c3cncc(Br)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (473 μL, 2.72 mmol) was added into a solution of 5-bromonicotinic acid (178 mg, 0.881 mmol), 4-((4-methylpiperidin-1-yl)methyl)benzenamine (150 mg, 0.734 mmol), BOP (487 mg, 1.10 mmol) in DMF (3 mL). The reaction mixture is stirred at rt under argon atmosphere overnight. The reaction mixture was diluted with 80 mL of AcOEt, and then washed with 1N NaOH aqueous solution three times. Organic phase was dried with anhydrous Na2SO4, and then evaporated to remove organic solvents. The obtained residue was further dried under high vacuum overnight to give crude product, which was used directly for the next step synthesis without further purification. MS (ESI+) m/z 388.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:16]=1[CH2:17][N:18]1[CH2:22][CH:21]([CH:23]([OH:25])[CH3:24])[CH2:20][C:19]1=[O:26]>ClCCl.O>[CH3:1][S:2]([O:25][CH:23]([CH:21]1[CH2:20][C:19](=[O:26])[N:18]([CH2:17][C:16]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:15]=2[O:14][CH3:13])[CH2:22]1)[CH3:24])(=[O:4])=[O:3]
Reactant: COc1ccc(CN2CC(C(C)O)CC2=O)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CC(C(C)OS(C)(=O)=O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
MsCl (3.3 g, 28 mmol) and Et3N (3.8 g, 38 mmol) were added to a mixture of 1-(2,4-dimethoxybenzyl)-4-(1-hydroxyethyl)pyrrolidin-2-one (5.0 g, 19 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 10 hours then diluted with water and extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford 1-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl]ethyl methanesulfonate. 1H NMR (400 MHz, CDCl3) δ 7.10˜7.13 (m, 1H), 6.43-6.45 (m, 2H), 4.76-4.78 (m, 1H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.36-3.42 (m, 1H), 3.12-3.19 (m, 1H), 2.98 (s, 3H), 2.23-2.59 (m, 3H), 1.26-1.42 (d, J=7.2 Hz, 3H). MS ESI calc'd. for C16H24NO6S [M+H]+ 358. found 358.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)[CH2:4]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of methyl (2-aminoindan-5-yl)acetate hydrochloride (2.43 g), potassium carbonate (5.52 g), water (60 ml), ethyl acetate (60 ml) and 4-chlorophenylsulfonyl chloride (2.11 g) is stirred at room temperature for one hour. The ethyl acetate layer is separated from the reaction mixture, washed with aqueous saline solution, dried, and distilled under reduced pressure to remove the solvent. The resulting crude product is recrystallized from a mixture of ethyl acetate and n-hexane to give methyl [2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (3.02 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([O:24]C)=[O:23])=[CH:21][C:16]=2[C:15](=[O:26])[N:14]([C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH3:28])[C@@H:13]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:12]1=[O:43])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=2[C:15](=[O:26])[N:14]([C@@H:27]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH3:28])[C@@H:13]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[C:12]1=[O:43])=[O:44])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2CCCCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(C(=O)O)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1
Yield: 77.4 %

Procedure:
A solution of 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-methoxycarbonyl-2,5-dioxo-3,4-dihydro-1H-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester (Example 32) (200 mg, 0.31 mmol) and NaOH (1N in water, 380 μL) in THF/MeOH/H2O (2 mL/400 μL/100 μL) was stirred at room temperature for 12 h. The mixture was evaporated to dryness. Then, the residue was dissolved in water (10 mL) and the pH was adjusted to 4 with 1N HCl. The solution was extracted with ether (3×20 mL), then the organic layer was dried (Na2SO4) and concentrated to dryness under reduced pressure. Filtration over silica gel afforded the title compound (150 mg, 77%): Mass spectrum (LCMS, ESI pos.): Calcd for C33H34Cl2IN2O6: 624.18; found 568.9 (M+H—t-bu).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Oc1cccc(F)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-fluoro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-fluoro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C@H:8](N)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O>[OH:14][C@@H:8]([CH2:7][CH:4]1[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[C:9]([OH:11])=[O:10]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)[C@@H](O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a stirring suspension of L-cyclohexylalanine (4.00 g,23.4 mmol) in 0.5M H2SO4 (120 mL) at 0° C. was slowly added dropwise an aqueous solution of NaNO2 (12.1 g in 40 mL H2O). Addition was complete after approximately 1 h, at which point the solution was allowed to warm to room temperature. After 16 h, the reaction mixture was extracted with ether (3×100 mL), and the combined organic extracts were washed with 1M NaHSO4 (1×200 mL) and brine (1×100 mL) and then dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the crude product was recrystallized from Et2O/pentane (10 mL/100 mL) to afford 2.1 g (52% yield) of (S)-2-hydroxy-3-cyclohexylpropionic acid as fine white needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2N2CCNCC2)=[CH:5][CH:4]=1.FC1C=CC(CC(O)=[O:28])=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[OH:28][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CCC2
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(O)CCC2
Yield: 129 %

Procedure:
7-Methoxy-1-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (0.6 g) was reacted in methylene chloride for 2 hr with an acid chloride prepared from 4-fluorophenylacetic acid (0.44 g) and thionyl chloride (0.21 ml) Then the liquid reaction mixture was partitioned between methylene chloride and water, extracted with methylene chloride, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene/acetone system) to give the title compound (0.56 g) as an oil. (280-5) 1-{4-[2-(4-Fluorophenyl)ethyl]piperdin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalene
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([S:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[N:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:33]1[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][S:30][C:20]1[N:19]=[C:18]([NH:17][S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:15])=[O:16])[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCC(F)(F)F)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(OCC(F)(F)F)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[[[2-[[(2,3-difluorophenyl)methyl]thio]-6-(2,2,2-trifluoroethoxy)-4-pyrimidinyl]amino]sulfonyl]-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step i) (0.21 g) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was evaporated, the residue was azeotroped with Et2O (×2) and then purified by reverse phase HPLC eluting with acetonitrile/aq. 0.2% trifluoroacetic acid mixtures to give title compound as a white solid. Yield: 0.14 g
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:2].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>C(O)C.Cl.C(O)(C)C.O>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH2:9][CH2:22][C:21]2[CH:24]=[C:25]([CH3:28])[C:26]([OH:27])=[C:19]([CH3:18])[CH:20]=2)=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCc1sc(C(C)=O)cc1-c1ccc(C)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccc(C)cc1
Reaction time: 18 h
Yield: 105.7 %

Procedure:
A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-ethanone (28 mg, 0.115 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (26 mg, 0.172 mmol) in ethanol (1.5 mL) and 5 N HCl in isopropanol (0.3 mL) is stirred at rt for 18 h. The solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (3 mL) and THF (3 mL) and treated with Pd/C (30 mg, 10% Pd). The slurry is stirred under 1.5 bar of H2 for 18 h. The mixture is filtered, the solvent of the filtrate is removed in vacuo and the crude product is purified by prep. HPLC to give 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (46 mg) as a colourless oil; LC-MS: tR=1.13 min, [M+1]+=379.22.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[CH2:13](NN(CC)NCC)[CH3:14].[C:22]1([S:28][CH:29]2CCCN[CH2:31][CH2:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:13]([N:10]([CH2:9][CH3:36])[CH2:11][CH2:12][NH:8][C:1]([N:3]1[CH2:4][CH2:31][CH2:30][CH:29]([S:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:6][CH2:7]1)=[O:2])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNN(CC)NCC
Reactant: c1ccc(SC2CCCNCC2)cc1
Agent: O=C(O)C(=O)O
Product: CCN(CC)CCNC(=O)N1CCCC(Sc2ccccc2)CC1

Procedure:
Following the procedure of Example 16, 1,1'-carbonyldiimidazole, N,N-diethylaminoethylamine and 4-(phenylthio)homopiperidine and oxalic acid are reacted to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:26]([O:27][CH3:28])[CH3:25])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccc(F)c1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 2-chloro-3-fluorobenzoic acid (30 g, 172 mmol) in 300 mL of DCM was added carbonyldiimidazole (CDI) (32.0 g, 198 mmol) in portions. After addition and then stirring at RT for 1 h, N,O-dimethylhydroxylamine HCl salt (18.5 g, 189 mmol) was added into the mixture followed by Et3N (20 mL). The mixture was stirred at RT overnight. After the reaction was quenched with water, the aqueous layer was extracted with DCM (2×). The organic layers were washed with 2N HCl (aq), water, sat. NaHCO3 (aq) and brine. The solution was dried (MgSO4) and concentrated. The product 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide (32.0 g) was obtained by silica gel chromatography (elution with 0-30% EtOAc/Hex).