Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:28][CH2:29][N:30]([CH:13]([CH3:15])[CH2:12][C:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=4)[CH2:31][CH2:32]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1cccc2c(CC(C)=O)coc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cccc2c(CC(C)N3CCN(c4cc(C)cc5cccnc45)CC3)coc12

Procedure:
6-methyl-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 40 mg (9%); (M+H): 416; 1HNMR (400 MHz, CDCl3): δ 8.86˜8.79 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 8.02˜7.56 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 7.56˜6.80 (m, 7 H), 3.89 (s, 3H), 3.50˜2.60 (m, 11H); 2.50 (s, 3H) 1.12˜114 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:4][CH2:3]1.Br[C:7]1[C:8]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[C:9]2[CH:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]2=[N:11][CH:12]=1.[NH4+].[Cl-]>C1COCC1.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>[CH:2]1([C:7]2[C:8]([N:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[C:9]3[CH:15]=[N:14][N:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:10]3=[N:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 75 °C
Yield: 59.6 %

Procedure:
Cyclopropylzinc(II) bromide (2.5 mL, 2.49 mmol) was added to a solution of tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (500 mg, 0.995 mmol) and Pd(PPh3)4 (86 mg, 0.075 mmol) in THF (5 mL) under N2. The reaction mixture was heated at 75° C. (oil bath) under N2 atmosphere for 18 hours. The reaction mixture was then allowed to cool to room temperature and poured into saturated aqueous NH4Cl (50 mL) solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit using a 15-90% CH3CN/water gradient (14 CV). The fractions containing the product were pooled, and the solvents were removed. The residue was evaporated from CH3CN (3×20 mL) and dried to provide tert-butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (275 mg, 60% yield) as a solid. LCMS (APCI+) m/z 464.2 (M+H)+, Rt=4.32 minutes.
Reaction SMILES: O=S1(=O)CCC(NCC[NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)C1.Cl[CH2:51][CH2:52][N:53]1[CH2:59][C:55]2([CH2:58][O:57][CH2:56]2)[CH2:54]1>>[CH2:58]1[C:55]2([CH2:59][N:53]([CH2:52][CH2:51][NH:10][C@:11]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]3[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28]4)[C@@:25]4([CH3:30])[C@@H:16]([C@:17]5([CH3:42])[C@@H:22]([CH2:23][CH2:24]4)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]4[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:40][CH:41]=4)=[CH:19][CH2:18]5)[CH2:15][CH2:14]3)[CH2:54]2)[CH2:56][O:57]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCN1CC2(COC2)C1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CC4(COC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane (prepared as described below) as the alkylating reagent in Step 3. The product was isolated as a white solid (1.1 mg, 18%). LCMS: m/e 655.53 (M+H)+, 2.29 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 5.37 (d, J=4.9 Hz, 1H), 4.93 (s., 4H), 4.86 (s, 1H), 4.75 (br. s., 1H), 4.71-4.32 (m, 4H), 4.05-3.86 (m, 2H), 3.70-3.40 (m, 2H), 3.00-2.66 (m, 1H), 2.25-1.05 (m, 22H), 1.76 (s, 3H), 1.18 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[CH2:34][CH2:33]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2C(C)(C)C)cc1

Procedure:
132 mg (91%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(2-fluorophenyl)piperazine (54 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [O-:1]Cl=O.[Na+].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)[CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]1.CC(=CC)C>O.CC(O)(C)C>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:1])=[O:32])=[CH:33][CH:34]=3)[CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C=O)cc2)cc1OC1CCCC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(=O)O)cc2)cc1OC1CCCC1
Yield: 101.8 %

Procedure:
A solution of NaClO2 (149 mg, 1.64 mmol) and NaH2PO4 ·H2O (227 mg, 1.64 mmol) in water (1 mL) was added to a solution of aldehyde from Step 3 (508 mg, 1.27 mmol) and 2-methyl-2-butene (0.94 mL, 8.9 mmol) in t-BuOH (6 mL). The reaction mixture was stirred at room temperature for 19 hours before 25% aqueous NH4OAc was added. The mixture was then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to afford the title compound as a white solid (540 mg). 1H NMR (400 MHz, CDCl3): δ 1.55 (m, 2H), 1.75 (m, 6H), 3.35 (m, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.60 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 7.00 (d, 2H), 7.25 (d, 2H), 8.00 (d, 2H), 8.45 (d, 2H).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>C1C=CC=CC=1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])=[CH:11][CH:10]=1
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(F)cc1

Procedure:
To a solution of 4.9 g. (0.05 mole) of 2 -imino-1 -methylpyrrolidine in anhydrous benzene is added 6.85 g. (0.05 mole) of p-fluorophenylisocyanate, dissolved in anhydrous benzene, dropwise with stirring. The mixture is stirred at room temperature overnight, then filtered and the filtrate taken to dryness in vacuo. The residue is triturated with isopropanol. The solid which forms is collected, 1 -p-fluorophenyl-3 -(1 -methyl-2 -pyrrolidylidene)urea, m.p. = 113°-115° C. Recrystallization from ethyl acetate yields the pure product, m.p. = 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[CH:19]=[CH:20][CH3:21].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:20]([CH3:21])[CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC=CCBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cl
Agent: [In]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.31 g; 1.09 mmol), crotyl bromide (1.2 mL; 11.8 mmol) and indium (1.26 g; 11.0 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude oil. The crude oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as a 2:1 mixture of diastereomers as an off-white solid.
Reaction SMILES: N#N.C(OC([NH:10][C@@H:11]([C:16]([N:18]([CH3:28])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=O)(C)(C)C.CCOCC>C(OCC)(=O)C.Cl>[CH3:28][N:18]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16](=[O:17])[C@@H:11]([CH2:12][CH2:13][S:14][CH3:15])[NH2:10]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)CCCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSCC[C@@H](N)C(=O)N(C)CCCc1ccccc1
Yield: 112.3 %

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N-methyl-N-(3-phenylpropyl)-D-methioninamide (4.06 g.) in hydrogen chloride-ethyl acetate (3.9 N, 20 ml.) was stirred at room temperature for 40 minutes. Ether (100 ml.) was added, precipitating an oil, and the mixture was stripped of volatiles under vacuum, affording N-methyl-N-(3-phenylpropyl)-D-methioninamide (3.13 g.).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15]([C:18]2[CH:19]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[S:21][CH:22]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:20]1[S:21][CH:22]=[C:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:19]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccccc2)cs1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(S(=O)(=O)c3ccccc3)cs2)c1Br
Yield: 26 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(benzenesulfonyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-benzenesulfonylthiophene-2-sulphonyl chloride in 26% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 181-184° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:20])[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][N:12]([C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CNCCN1
Reactant: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-[N-methyl-N-(3-picolyl)-amino]-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 154°-156° C.) and piperazine.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH2:17])[C:10]=2[CH:9]=1.C(N(CC)CC)C>C1COCC1>[F:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[C:10]=2[CH:9]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NC1CCCCc2ccc(F)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NC1CCCCc2ccc(F)cc21
Reaction time: 8 h
Yield: 71.2 %

Procedure:
2.3 g (18 mmol) of ethanesulfonyl chloride were added dropwise with ice-cooling to a solution of 2.68 g (15 mmol) of 3-fluoro-5-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene and 1.5 g (60 mmol triethylamine in 40 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the precipitated product was filtered off with suction. 2.9 g of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene were obtained, m.p. 118-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1.[S:13]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B(O)O)=[CH:24]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:7]=[C:2]([C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]([S:13]([C:16]4[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH:24]=3)[CH:3]=[N:4][CH:5]=2)=[CH:9]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B(O)O)c3ccccc32)cc1
Reactant: Brc1cncc(-c2ccsc2)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: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(-c4ccsc4)c3)c3ccccc32)cc1

Procedure:
A deoxygenated solution of 3-bromo-5-thiophen-3-yl-pyridine (250 mg, 1.04 mmol, 1 equiv), 1-tosyl-3-indoleboronic acid (430 mg, 1.36 mmol, 1.31 equiv, prepared according to Zheng, Q; Yang, Y; Martin, A. R. Heterocycles 1994, 37, 1761), Pd(PPh3)4 (60 mg, 0.052 mmol, 0.050 equiv), and 2.0 M Na2CO3 (1.0 mL, 2.0 mmol, 1.9 equiv) in dioxane (10 ml) was heated under argon at reflux for 20 h. The reaction mixture was allowed to cool, then partitioned between water (100 mL) and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (40% ethyl acetate in hexane) to afford 3-(5-thiophen-3-yl-pyridin-3-yl)-1-(toluene-4-sulfonyl)-indole as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37]C(C)(C)C)=[O:36])=[C:33]([F:44])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([OH:37])=[O:36])=[C:33]([F:44])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:45])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 6 h
Yield: 95.3 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluorobenzoate (170 mg, 257 μmol, Eq: 1.00) was combined with CH2Cl2 (3 mL) to give a colorless solution. TFA (3 ml) was added and the reaction was stirred for 6 hours. The crude reaction mixture was concentrated in vacuum, added DCM and concentrated again. Recrystallization from diethyl ether and hexanes afforded a white solid (148 mg, 93% yield). MS (ES+) m/z Calcd: [(M+H)+]: 604. found: 604.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([OH:32])=[C:28]([C:33](OC)=[O:34])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.CO>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH:28]([CH2:33][O:34][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C1=C(O)CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
0.82 g of imidazole and 0.72 g of tert-butyldimethylchlorosilane were added to N,N-dimethylformamide (10 mL) solution of 1.0 g of methyl 1-benzyl-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate, and stirred at room temperature for 0.5 hours, and then methanol was added thereto. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was dissolved in 30 mL of diethyl ether, and with cooling with ice, 0.30 g of lithiumaluminium hydride was added thereto, and stirred at that temperature for 1.5 hours, and then methanol was added thereto. The reaction solution was diluted with ethyl acetate, then washed with water and saturated saline water in that order, dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. High-polarity side products were removed from the resulting residue through silica gel column chromatography (chloroform/methanol=10/1), and the residue was dissolved in 10 mL of N,N-dimethylformamide, and 0.41 g of imidazole and 0.72 g of tert-butyldimethylchlorosilane were added thereto, and stirred at room temperature for 10 minutes. Water was added to the reaction solution, and diluted with ethyl acetate. Then, this was washed with water and saturated saline water in that order, dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=10/1 to 4/1) to obtain 566 mg of the entitled compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]1[S:11][CH:12]=[C:13]([C:15]#[CH:16])[N:14]=1.C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:16]#[C:15][C:13]2[N:14]=[C:10]([CH3:9])[S:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: C#Cc1csc(C)n1
Reactant: Clc1ncc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2cnc(Cl)nc2)cs1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-5-bromopyrimidine (5.0 g, 26 mmol), 2-methyl-4-ethynyl-1,3-thiazole (3.2 g, 26 mmol), tetrakis(triphenylphosphine)palladium (0) (0.6 g, 0.5 mmol), copper (I) iodide (0.1 g, 0.5 mmol) and triethylamine (13 g, 130 mmol) were added to deoxygenated toluene (50 mL) at room temperature. The reaction was then warmed to 60° C. Stirring continued for 2.5 hrs and the reaction contents were then poured in to a separatory funnel and partitioned with EtOAc (100 mL) and water (100 mL). The organic layer was then washed with water twice (250 mL each). The organic layer were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with 1:1 EtOAc:hexanes to afford 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 8.78 (s, 2H), 7.52 (s, 1H), 2.78 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([OH:16])=O)=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH:21]1([CH2:24][NH2:25])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][NH:25][C:14]([C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]([CH3:12])[C:8]=2[CH3:13])=[O:16])[CH2:23][CH2:22]1
Reactant: NCC1CC1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(C(=O)NCC3CC3)c(C)n(C)c2c1
Yield: 38.4 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.80, 3.65 mmole) with SOCl2 (0.799 ml, 10.95 mmole) and cyclopropylmethylamine (0.38 ml, 4.38 mmole) in a manner as previously described for example 9d to give a pale yellow solid (0.382 g, 38%). 1H NMR (300 MHz, CD3OD) δ 7.50 (1H, d, J=8.7 Hz), 6.81 (1H, d, J=2.2 Hz), 6.69 (1H, dd, J=2.2, 8.7 Hz), 3.74 (3H, s), 3.56 (3H, s), 3.20 (2H, m), 2.50 (3H, m), 1.07 (1H, m), 0.44 (2H, m}, 0.21 (2H, m); ESIMS (MH+): 273.10.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C(=O)C.O.CO>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]([C:16](=[O:18])[CH3:17])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ccc(O)c(F)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CN(C(C)=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl(3-fluoro-4-hydroxyphenylamino)acetate (0.84 g, 4 mmol) was dissolved in N,N-dimethylacetamide (4 mL). To the resulting solution was added acetyl chloride (0.6 mL, 10 mmol), and the resulting solution was stirred at room temperature for 1 hour. Water (1 mL), methanol (10 mL) and saturated sodium carbonate (10 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the solution. 10% hydrochloric acid was employed to turn the solution acidic, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane 2:1), to thereby yield 0.84 g of the title compound.