Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:13][CH2:12][C:11]([CH3:14])=[CH:10][CH2:9][CH2:8][C:7]([CH3:15])=[CH:6][CH2:5][CH2:4][CH:3]=1.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH2:13]1)[CH3:17]
Reactant: CCO
Reactant: CC1=CCCC=C(C)CCC(C)=CCC1
Product: CCOC1(C)CCCC=C(C)CCC=C(C)CC1
Yield: 63 %

Procedure:
550 g (2.7M) of 2,5,9-trimethyl-cyclododeca-1,5,9-triene and 380 g of acidic diatomaceous earth in 6250 ml of anhydrous ethanol were refluxed for 72 h to give, after the same treatment as that described in Example 1 above, 532 g of a product having b.p. 70°-110°/0.01 Torr. On fractional distillation, there were recovered 495 g of starting 2,5,9-trimethyl-cyclododeca-1,5,9-triene (b.p. 43°-52°/0.1 Torr) and 42.5 g of the desired product (b.p. 90°-105°/0.01 Torr); yield 63% based on the converted starting material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].CCN(C(C)C)C(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (81 mg, 0.252 mmol), n,n-diisopropylethylamine (0.22 ml, 1.26 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (81 mg, 0.25 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (141 mg, 0.302 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (47 mg, 0.080 mmol, 31.6% yield) as a clear oil: LCMS (ES) m/e 589, 591 (M, M+2)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:20](=[O:43])[NH:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][OH:27])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(C)(C)C.N[C@@H](CC1C=CC2C(=CC=CC=2)C=1)C(NCCCC[C@H](N(S(C1C=CC(N)=CC=1)(=O)=O)CC(C)C)CO)=O>>[NH2:7][C@@H:8]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:20]([NH:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:28]([S:33]([C:36]1[CH:37]=[CH:38][C:39]([NH2:42])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][OH:27])=[O:43]
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (1S,4S)-(1-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentylcarbamoyl}-2-naphthalen-1-yl-ethyl)-carbamic acid tert-butyl ester as described for the preparation of (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 49). The final product was obtained in 94% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][OH:17])[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: CCOc1ccccc1CO
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: CCOc1ccccc1COc1ccncc1[N+](=O)[O-]
Yield: 65.9 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 2-ethoxybenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 65.9%)
Reaction SMILES: [NH2:1][CH:2]([CH2:13][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][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)=[CH:18][C:17]=1[Cl:37])[CH2:3][O:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:5]([O:4][CH2:3][CH:2]([NH:1][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][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][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)=[CH:18][C:17]=1[Cl:37])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)COC(=O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: O=C(OCC(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 145.7 %

Procedure:
The compound of Example 128-1 (670 mg) was dissolved in methylene chloride (30 mL). To this solution, Ph3Bi(OAc)2 (558 mg) and copper acetate (10 mg) were added and the mixture was stirred at room temperature for 1 day. Subsequently, the solvent was removed and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the desired product as a colorless oil (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.CN(C=O)C.C(Cl)(C([Cl:44])=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:44])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:29])([F:30])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)O)ccc2Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution was prepared using 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoic acid (0.100 g, 0.204 mmol), DMF (0.100 mL), (COCl)2 (2.0 mL, 21.0 mmol) and anhydrous CH2Cl2 (25 mL). The mixture was stirred at rt and for a period of 16 h and concentrated to dryness. The resulting product was used without purification (0.113 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]1[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)C>C1COCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:10][OH:9])[CH:13]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)C(NCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a solution of LiAlH4 (2M in THF, 14 mmol in 25 ml THF), cooled to 0° C., was slowly added a solution of 3-benzylamino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.53 g, 12.5 mmol) in THF (25 mL). The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was again cooled to 0° C. and quenched with Na2SO4, 10 H2O and stirred for 16 h. The reaction mixture was filtered, washed with THF and concentrated to yield title compound (3.69 g, 92%). MS (ESI) mass calcd. for C18H28N2O3, 320.43; m/z found, 321.3 [M+H]+. 1H NMR (CDCl3): 7.42-7.19 (m, 5H), 5.64-4.97 (m, 1H), 4.57-4.0 (m, 1H), 3.99-3.82 (m, 2H), 3.79-3.56 (m, 3H), 3.04-2.58 (m, 3H), 1.95-1.79 (m, 2H), 1.74-1.55 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[SH:30]>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Sc1ccc2ccccc2c1
Product: O=C(O)CNC(=O)c1nc(Sc2ccc3ccccc3c2)c2ccccc2c1O

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 2-napthalenethiol under conditions analogous to Example D-110. The final product was purified by triturating the crude product twice with methanol and twice with dichloromethane; MS (+) m/z 405.08 (M+1).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[SH:4][C@@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](CN2CCNC2=O)N(C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1C[C@@H](S)C[C@H]1CN1CCNC1=O
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.83 g) in methanol (20 ml) was added 28% sodium methoxide in methanol solution (1.50 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added acetic acid (0.45 ml) at the same temperature and the mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (0.60 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]([CH2:36][OH:37])[CH2:38][CH:39]([CH3:40])[CH3:41])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Product: CC(C)C[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (S)-2-bromo-N-(1-hydroxy-4-methylpentan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H25FN4O3S, 444.16; m/z found, 445.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.29 (d, J=1.4, 1H), 8.16-8.12 (m, 1H), 7.98-7.92 (m, 1H), 7.68-7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.40-7.28 (m, 3H), 3.41-3.34 (m, 1H), 3.29-3.22 (m, 2H), 1.59-1.47 (m, 1H), 1.35-1.17 (m, 2H), 0.81 (d, J=6.7, 3H), 0.73 (d, J=6.5, 3H).
Reaction SMILES: [C:1](=O)([O-])O.[Na+].CI.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][CH2:26][C:27]([C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[C:31]([OH:33])=[O:32])=[O:28])[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9].O>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][CH2:26][C:27]([C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[C:31]([O:33][CH3:1])=[O:32])=[O:28])[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]
Reactant: O=C([O-])O
Reactant: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C(=O)O)cs2)cc1OCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C(=O)OC)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Sodium hydrogencarbonate (79 mg, 0.94 mmol) and methyl iodide (0.04 ml, 0.56 mmol) were added to a solution (4 ml) of 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoic acid (200 mg, 0.47 mmol) in DMF, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol, to thereby obtain 190 mg (yield: 92%) of methyl 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoate as colorless needles.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[N+:19]([O-])=O)[CH2:15][CH:14]([CH2:22][CH3:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt]>[CH2:1]([O:8][C:9]1[C:18]([NH2:19])=[CH:17][C:16]2[CH2:15][CH:14]([CH2:22][CH3:23])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CCc2cc(OCc3ccccc3)c([N+](=O)[O-])cc2C1
Agent: [Pt]
Product: CCC1CCc2cc(OCc3ccccc3)c(N)cc2C1
Reaction time: 18 h

Procedure:
To a solution of 6-benzyloxy-2-ethyl-7-nitro-1,2,3,4-tetrahydronaphthalene (490 mg, 1.57 mmol) is added 5% Pt/C (680 mg) and stirred under hydrogen atmosphere (1 atm) for 18 h. It is then filtered through Celite and the filtrate is concentrated. The residue is purified by column chromatography to give the title compound as a brown solid.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:46])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])=[N:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:1]1([C@H:7]([NH:9][C:10](=[O:46])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])=[N:19][NH:20][C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(NC(=O)C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(NC(=O)C3CC3)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
(R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxamide (0.037 mmol) was taken up in TFA (1 ml) and the reaction mixture was stirred at room temperature for 1 h. Triethylsilane (0.006 ml, 0.037 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered preparative HPLC to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxamide (4.3 mg, 0.012 mmol, 31.8% yield) as a white solid. MS ESI calc'd. For C19H21N6O2 [M+H]+ 365. found 365. 1H NMR (ppm, 600 MHz, DMSO): δ 11.15 (s, 1H); 9.33 (br s, 1H); 9.05 (s, 1H); 7.79 (br s, 1H); 7.41 (s, 1H); 7.31 (d, J=4.4 Hz, 4H); 7.21 (d, J=5.7 Hz, 1H); 4.84 (t, J=7.2 Hz, 1H); 1.93 (m, 1H); 1.38 (d, J=7.0 Hz, 3H); 0.83 (t, J=6.9 Hz, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](OC)=[O:21])[CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].O.[OH-].[Na+]>C1COCC1>[CH3:7][S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9]
Reactant: COC(=O)c1ccc2ccn(S(C)(=O)=O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)n1ccc2ccc(CO)cc21
Reaction time: 0.5 h

Procedure:
A solution of lithium aluminum hydride (1 M) in THF (2.57 mmol, 2.57 ml) was added dropwise to a 0° C. solution of N-methanesufonyl-6-carbomethoxyindole in dry THF (10 mL, from above). After 30 min, 0.5 ml of water was added dropwise followed by the addition of 0.5 ml 1.0 M NaOH solution. Celite was added and the mixture was filtered through a coarse fritted funnel. The solids were washed with 20 ml ethyl acetate. The filtrate was concentrated under vacuum. The product was purified by flash column chromatography (silica gel, applied to column with toluene, gradient elution 20-50% ethyl acetate/hexane) to give 370 mg of N-methanesulfonyl-6-hydroxymethylindole, a white solid (80% yield).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC.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>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:19]3[CH:20]=[N:21][CH:22]=[C:17]([CH3:16])[CH:18]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Reactant: Cc1cncc(B(O)O)c1
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: COCCOC
Solvent: O
Product: Cc1cncc(-c2nc3c(C)c(F)ccc3cc2C=O)c1
Yield: 79.8 %

Procedure:
Prepared according to the procedure described for Intermediate 41, utilising 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (5.0 g, 22.36 mmol), 5-methylpyridin-3-ylboronic acid (6.95 g, 50.75 mmol), tetrakis(triphenylphosphine)palladium(0) (258 mg, 0.22 mmol) and Na2CO3 (3.55 g, 33.54 mmol) in water (30 mL) and DME (60 mL). The crude material was triturated in diethyl ether (75 mL), and the solid was filtered off and dried under vacuum to give the title compound (5.0 g, 80%) as a brown solid. δH (DMSO-d6) 10.12 (s, 1H), 9.06 (s, 1H), 8.72 (d, J 1.9 Hz, 1H), 8.60 (d, J 1.5 Hz, 1H), 8.24 (dd, J 9.0, 6.4 Hz, 1H), 7.99 (d, J 0.6 Hz, 1H), 7.68 (t, J 9.2 Hz, 1H), 2.66 (d, J 2.4 Hz, 3H), 2.44 (s, 3H). LCMS (ES+) 281 (M+H)+, RT 1.66 minutes.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[F:20][C:21]([F:28])([F:27])[C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:9][O:8][C:7]1[C:3]([CH2:2][N:24]2[CH:25]=[CH:26][C:22]([C:21]([F:28])([F:27])[F:20])=[N:23]2)=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc(C(F)(F)F)n1
Temperature: 55 °C
Reaction time: 1.25 h

Procedure:
To a solution of 4-(bromomethyl)-5-methoxy-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole (i.e. the product of Example 1, Step D) (0.25 g, 66 weight %, 0.5 mmol) in N,N-dimethylformamide (2 mL total), was added 3-(trifluoromethyl)pyrazole (0.082 g, 0.6 mmol) and anhydrous potassium carbonate (0.21 g, 1.5 mmol). The mixture was heated to 55° C. and stirred for 75 min. The reaction mixture was cooled to 23° C., diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 40% ethyl acetate in hexanes to afford the title compound (0.098 g) as a colorless oil.
Reaction SMILES: O[C@H:2]1[CH2:7][C@@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.[CH2:14]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[CH2:14]([N:16]([C@H:2]1[CH2:7][C@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2)[S:17]([C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)(=[O:18])=[O:19])[CH3:15]
Reactant: C[C@@H]1C[C@H](O)c2ccsc2S1(=O)=O
Reactant: CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN([C@H]1C[C@H](C)S(=O)(=O)c2sccc21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Yield: 50.4 %

Procedure:
Methylene chloride (60 mL), cis-4-hydroxy-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide (5 g), N-ethyl-4-nitrobenzene-sulfonamide (6.86 g) and triphenyl-phosphine (8.42 g) are mixed under nitrogen atmosphere. The mixture is cooled to under −20° C. and diisopropyl azadicarboxylate (5.9 mL) is added, maintaining the temperature under −20° C. The temperature is allowed to rise to 20-25° C. The obtained mixture is treated with 5% NaOH (125 mL) and the resulting organic phase is vacuum distilled to dryness. The residue is chromatographed in a column (ethyl acetate/heptane, 2/1), obtaining 4.97 g of trans-4-[N-ethyl-N-(4-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:9]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH:1]1([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCCCC2)C1

Procedure:
Reaction of cyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.