Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[OH:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:44]4[CH2:45][CH2:46][C@@H:42]([OH:41])[CH2:43]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(-c3ccc(CN4CC[C@@H](O)C4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.7 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (0.075 g, 0.14 mmol), (S)-3-hydroxypyrrolidine (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of (S)-3-hydroxypyrrolidine (0.1 mL) and sodium triacetoxyborohydride (0.084 g, 0.40 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the reaction mixture was concentrated in vacuo. The residue was dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 16.5-18.4 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(3R)-3-hydroxytetrahydro-1H-1-pyrrolyl]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.027 g, 0.043 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.89 (1H, s), 8.30-8.33 (2H, m), 8.13-8.14 (2H, m), 7.90-7.80 (1H, m), 7.84 (1H, d, J=10.8 Hz), 7.70 (1H, d, J=7.6 Hz), 7.35-7.59 (4H, m), 4.64 (1H, bs), 4.14-4.23 (1H, m), 3.91 (3H, s), 3.62 (2H, s), 2.61-2.62 (2H, m), 2.27-2.28 (2H, m), 2.27-2.28 (2H, m), 2.02 (1H, m), and 1.60 (1H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.41 min. MS: MH+ 622.2.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[C:4]([CH3:40])[CH:3]=1.O.[C:42](=O)([O-:44])[O-:43].[K+].[K+].[C]=O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C@@:15]2([C:25]#[N:26])[C@H:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13][C@@H:12]([C:10]([NH:9][C:5]3[C:4]([CH3:40])=[CH:3][C:2]([C:42]([OH:44])=[O:43])=[C:7]([CH3:8])[CH:6]=3)=[O:11])[C@@H:16]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])=[C:28]([F:34])[CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)c(C)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)O)c(C)cc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 70 °C
Yield: 34.2 %

Procedure:
To a solution of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-2,5-dimethyl-phenyl)-amide (Example 365, 149 mg, 0.214 mmol) in DMF (5 ml) was added water (0.2 ml), and potassium carbonate (60 mg, 0.428 mmol). The mixture was bubbled with nitrogen and palladium acetate (5 mg, 0.021 mmol) was added. The mixture was subjected to carbon monoxide atmosphere at 50 psi and was heated at 70° C. for 3 h. The mixture was then filtered through celite, acidified with HOAc and extracted with EtOAc (3×10 ml). The organic solution was concentrated and was purified by reverse phase HPLC using acetonitrile and water. Obtained the title compound as a white powder, (45 mg, 35% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C1COCC1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O.O>[CH2:20]([O:1][CH:2]1[CH2:3][NH:4][CH2:5]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(COC2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 3-hydroxyazetidine-1-carboxylate (3.0 g) was mixed with THF (30 ml), and sodium hydride (55% suspended in oil) (600 mg) was added thereto, followed by stirring at room temperature for 10 minutes. Benzyl bromide (2.5 ml) was added thereto, followed by stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (15 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 3-(benzyloxy)azetidine (2.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([CH:40]5[CH2:42][CH2:41]5)[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnn2c(C3CCN(C4CC4)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 50.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.20 mmol) in MeOH (2.25 mL) containing 3 Å molecular sieves was added AcOH (114 μL, 2.00 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (241 μL, 1.20 mmol) and sodium cyanoborohydride (57 mg, 0.90 mmol). The reaction was stirred at 60° C. for 17 h. The mixture was quenched with the addition of saturated, aqueous NaHCO3 (10 mL) and was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 47 mg (51%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 825 (s, 1 H), 7.60 (s, 1 H), 7.50 (d, 1 H), 7.28 (s, 1 H), 6.98-7.08 (m, 5 H), 6.84 (dd, 1 H), 6.27 (s, 1 H), 5.35 (s, 2 H), 3.04 (s, 2 H), 2.72 (s, 2 H), 1.99 (s, 2 H), 1.66 (s, 2 H), 1.27-1.38 (m, 2 H), 0.13 (s, 1 H), 0.11 (d, 1 H), −0.03-0.03 (m, 2 H); ES-MS m/z 464.32 [M+H]+, HPLC RT (min) 1.24.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:73])[NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:59]=[C:58]3[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]3=[O:60])=[CH:53][CH:52]=2)=[C:47]([C:69]([F:72])([F:71])[F:70])[CH:46]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:73])[NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:59]=[C:58]3[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([OH:64])=[O:63])[C:57]3=[O:60])=[CH:53][CH:52]=2)=[C:47]([C:69]([F:71])([F:72])[F:70])[CH:46]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cc3C(F)(F)F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cc3C(F)(F)F)cc2C1=O
Yield: 97 %

Procedure:
The compound of example 416 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 415.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:4]=2[O:3]1.[Cl:17]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[C:10]([Cl:17])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:4]=2[O:3]1
Reactant: CC1(C)CCCc2cccc(C(=O)O)c2O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCCc2cc(Cl)cc(C(=O)O)c2O1
Reaction time: 48 h

Procedure:
To a solution of 3.6 g (16.4 mmol) of 2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 20 ml of DMF is added 2.6 g (19.7 mmol) of N-chlorosuccinimide in one portion at room temperature. The resulting solution is stirred for 31/2 days. The reaction mixture is then diluted with ethyl acetate washed with water, and the organic layer is dried (MgSO4), filtered and concentrated to obtain 2,2-dimethyl-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH2:37][O:38][CH3:39])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH2:37][O:38][CH3:39])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COCOc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
A mixture of {1-benzyl-3-([4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl]oxy)-1H-pyrazol-4-yl}methanol (0.80 g), activated manganese dioxide (2.50 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-([4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl]oxy)-1H-pyrazole-4-carbaldehyde (0.70 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[N:5]2)[CH2:3][CH2:2]1.[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:6]3[CH:7]=[CH:8][N:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)=[O:11])[CH3:29])[N:16]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccn(C2CC2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(C2CC2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 1-cyclopropyl-1H-pyrazole-3-carboxylic acid (0.300 g, 1.8 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile (0.471 g, 1.8 mmol). The product was purified by flash-chromatography. Yield: 400 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.98-1.11 (m, 7H), 3.75-3.80 (m, 1H), 4.25-4.48 (m, 3H), 6.54 (d, 1H), 6.96 (d, 1H), 7.82 (d, 2H), 7.93-7.99 (m, 2H), 8.07 (s, 1H), 8.16 (d, 1H), LC-MS: [M+1]=395.15.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncsc1-c1cccc(I)c1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncsc1-c1cccc(I)c1
Yield: 88.1 %

Procedure:
Reaction of 5.0 g (15.1 mmol) of 5-(3-iodophenyl)-4-thiazolecarboxylic acid with 2.6 g (16.2 mmol) of t-butyl (2-aminoethyl)carbamate in an analogous manner to that described in Example 1(E) yielded 6.3 g (88.1%) of t-butyl [2-[5-(3-iodophenyl)-4-thiazolecarboxamido]ethyl]carbamate as white crystals, melting point 111°-112°.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:23][O:24][CH2:25][CH:26]1[CH2:28][O:27]1.Cl>C1COCC1>[CH3:23][O:24][CH2:25][CH:26]([OH:27])[CH2:28][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1
Reactant: COCC1CO1
Reactant: c1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC(O)Cc1ccnn1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To an THF solution (450 ml) of 1-phenylpyrazole (15 g) was added 1.6M butyllithium/hexane solution at −78° C., and the mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added 2-(methoxymethyl)oxirane (27.8 ml) at −78° C., and the mixture was allowed to be warmed to room temperature, and stirred for 1 hr. To the reaction mixture was added 1N hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.2 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH:18]=[C:17]([C:19](OCC)=[O:20])[C:16]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH:18]=[C:17]([CH2:19][OH:20])[C:16]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Lithium aluminium hydride (6.64 g) was added to a solution of ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (58.90 g) in tetrahydrofuran (500 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was poured into water and the precipitate was removed by filtration, the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)methanol (45.30 g, yield: 88%) was obtained as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 79–80° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O.C(Cl)(Cl)Cl>C1C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][Cl:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCl)cc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 98.5 %

Procedure:
To a cooled solution of 3-[(tert-Butyldimethylsilyl)oxy]-4-methoxybenzyl alcohol 14 (9.5 g, 35.4 mmol) in benzene (50 mL) under nitrogen, thionyl chloride (6.32 g or 3.87 mL, 53.1 mmol) dissolved in benzene (5 mL) was added over 10 min and maintained the temperature at 0° C. for 2 h. The completion of reaction was checked by TLC (chloroform on silica gel plate). Ice was added to the reaction mixture and the solution was extracted with ethylacetate. The organic layer was washed with saturated bicarbonate solution and water and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded 15. Yield: 98.5%; yellow oil. 1H NMR: δ 0.16 (s, 6H, 2×CH3), 1.00 (s, 9H, 3×CH3), 3.80 (s, 3H, OCH3), 4.44 (s, 2H, CH2), 6.70-7.01 (m, 3H, Ar—H). Anal. Calcd for C14H23ClO2Si: C, 58.62, H, 8.08. Found: C, 58.69, H, 8.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH2:100][CH3:101])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH2:92])(=[O:91])=[O:90])=[CH:85][C:84]=1[S:93]([C:96]([F:99])([F:98])[F:97])(=[O:95])=[O:94])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH2:100][CH3:101])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH:92][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:90])=[O:91])=[CH:85][C:84]=1[S:93]([C:96]([F:98])([F:99])[F:97])(=[O:94])=[O:95])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:64])([CH3:66])[CH3:65])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 130, 0.12 g, 0.23 mmol), DMAP (56 mg, 0.46 mmol), and EDC (88 mg, 0.46 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (3.0 ml) and DIPEA (0.08 ml, 0.46 mmol) were added, and the solution was stirred at r.t for 15 min. A solution of (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 25, 0.18 g, 0.23 mmol) in DCM (1.5 ml) was added to the solution and the reaction mixture was stirred at r.t overnight. The reaction mixture was diluted with DCM and washed with sodium bisulfate (1N, aq.) followed by sodium bicarbonate (saturated, aq). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue that was dried under vacuum to provide N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 12, STEP 1, 0.31 g) which was used in the preparation of EXAMPLE 12, STEP 2 without further purification.
Reaction SMILES: FC(F)(C1C=C2C(=CC=1)N=CC(OC)=C2)C(NNC1C=C(C2C=NN(C)C=2)C=CC=1F)=O.[F:33][C:34]([F:50])([C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][C:42]([O:48][CH3:49])=[CH:41]2)[C:35]([OH:37])=O.S(Cl)(Cl)=O.C(N(CC)CC)C.[F:62][C:63]1[C:64]([NH:75][NH2:76])=[N:65][CH:66]=[C:67]([C:69]2[CH:70]=[N:71][N:72]([CH3:74])[CH:73]=2)[CH:68]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO.CN(C=O)C>[F:50][C:34]([F:33])([C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][C:42]([O:48][CH3:49])=[CH:41]2)[C:35]([NH:76][NH:75][C:64]1[C:63]([F:62])=[CH:68][C:67]([C:69]2[CH:70]=[N:71][N:72]([CH3:74])[CH:73]=2)=[CH:66][N:65]=1)=[O:37]
Reactant: Cn1cc(-c2cnc(NN)c(F)c2)cn1
Reactant: COc1cnc2ccc(C(F)(F)C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: COc1cnc2ccc(C(F)(F)C(=O)NNc3cc(-c4cnn(C)c4)ccc3F)cc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cnc2ccc(C(F)(F)C(=O)NNc3ncc(-c4cnn(C)c4)cc3F)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
2,2-difluoro-N′-(2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(3-methoxyquinolin-6-yl)acetohydrazide. A round bottom flask was charged with 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid (389 mg, 1536 μmol) and DMF (8 mL). The solution was cooled to 0 C, thionyl chloride (224 μl, 3073 μmol), was added and the resulting solution was maintained 1 h at 0° C. Then, triethylamine (641 μl, 4609 μmol) was added via syringe, followed by 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (382 mg, 1844 μmol) and 4-(dimethylamino)pyridine (18.8 mg, 154 μmol); both added as solids. The heterogeneous solution was stirred at 0° C. for 1 h, then allowed to warm to rt and stir for 18 h. The mixture was quenched with saturated aqueous NaHCO3 (50 mL) and the resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were concentrated (heating to 50° C.) and the residue purified by SiO2 chromatography solvent system: CH2Cl2:MeOH 99%:1% gradient 90:10 CH2Cl2 to yield 2,2-difluoro-N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide (225 mg, 33.1% yield) as a brown amorphous solid.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[CH:12]([OH:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])(=O)=O>C1(C)C=CC=CC=1>[Si:53]([O:36][CH:12]1[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]2[N:7]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]1=2)([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
0.529 g (1 mmol) of [2-cyclopentyl-4-(3,4-difluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-3-yl]-(4-trifluoromethylphenyl)-methanone are dissolved in 6 ml of abs. toluene and admixed with 0.465 ml of lutidine at −5° C. At from −5° C. to −10° C., 0.459 ml (2 mmol) of tert-butyldimethylsilyl trifluoromethanesulphonate is added. The mixture is stirred at 20° C. for 3 hours. The mixture is diluted with toluene, the reaction is quenched with 10% strength aqueous ammonium chloride solution and the organic phase is washed with 0.1 N hydrochloric acid and saturated aqueous sodium bicarbonate solution and dried. The solvent is distilled off under reduced pressure and the residue is then purified using a column. This gives 620 mg of colourless crystals of melting point: 128° C.-129° C.