Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:40]1[CH2:45][CH2:44][O:43][CH2:42][CH:41]1[C:46]1[C:54]2[S:53][C:52]([NH2:55])=[N:51][C:50]=2[C:49]([O:56][CH3:57])=[CH:48][CH:47]=1>C1COCC1.C(Cl)(Cl)Cl>[O:40]1[CH2:45][CH2:44][O:43][CH2:42][CH:41]1[C:46]1[C:54]2[S:53][C:52]([NH:55][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[N:51][C:50]=2[C:49]([O:56][CH3:57])=[CH:48][CH:47]=1
Reactant: COCC(=O)O
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1

Procedure:
From methoxyacetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.9° (c=1.05, CHCl3), ES-MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH:17]([C:19]1[N:20]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1)=O.O>O1CCCC1>[C:24]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1/[CH:17]=[CH:7]/[C:6]([O:5][CH2:3][CH3:4])=[O:16])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.811 g, 20.3 mmol) in tetrahydrofuran (60 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (4.33 ml, 21.8 mmol) and the mixture was stirred for 30 min. A solution of 2-formyl-1-tritylimidazole (5.28 g, 15.6 mmol) in tetrahydrofuran (30 ml) was added dropwise and the mixture was stirred for 8 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (9:1-1:1, v/v). The title compound (3.28 g, 52%) was obtained as a colorless powder from the object fraction.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:9])[CH3:8])=[CH:2][CH:3]=1)=[O:17]
Reactant: CC(C)c1ccccc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)CBr)cc1
Temperature: -10 °C
Yield: 99.5 %

Procedure:
To a solution of cumene (42 g, 350 mmol) and aluminum chloride (56.0 g, 420 mmol) in dichloromethane (500 mL) was added bromoacetylbromide (33.5 mL, 385 mmol) at −40° C. for 40 minutes, and the mixture was stirred until it was warmed to −10° C. for 2 hours. The reaction solution was poured into ice-cold water to separate the organic layer. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, and then was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 84 g (yield 99%) of the title compound. Oily matter.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:45]=[N:46][CH:47]=[N:48][CH:49]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:45]=[N:46][CH:47]=[N:48][CH:49]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:10][CH2:11]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Brc1cncnc1
Product: COc1ccc(-c2cncnc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (275 mg, 0.44 mmol) is coupled to 5-bromopyrimidine (79 mg, 0.48 mmol) using Method B to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[S:15])([CH3:3])[CH3:2].Cl.C([O:19][C:20](=O)[CH2:21][NH:22][CH3:23])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]1[C:20](=[O:19])[CH2:21][N:22]([CH3:23])[C:14]1=[S:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)CN(C)C1=S
Yield: 60.2 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 8.3 g of 2,6-diisopropylphenyl-isothiocyanate, 5.8 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether/hexane mixture afforded the title compound (6.6 g) as a tan solid, m.p. 174°-176° C. Anal. Calcd. for C16H22N2OS: C, 66.17; H, 7.63; N, 9.64. Found: C, 66.39; H, 7.63; N, 9.59. Mass spectrum (+FAB, [M+H]+) m/z 269/271.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C([Mg]Cl)(C)C.Cl[Sn:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH3:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[CH:7]=[C:2]([Sn:17]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: CSc1cc(I)nc(C)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A solution of 4-iodo-2-methyl-6-(methylthio)pyrimidine (2.35 g, 8.83 mmol) in THF (20 mL) was cooled to −78° C. and treated dropwise with isopropylmagnesium chloride (2 N solution in THF, 2 mL, 4.0 mmol, Aldrich). After 10 min, chlorotributylstannane (2.4 mL, 8.83 mmol, Aldrich) was added. The mixture was stirred at −78° C. for 1 h, then warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by flash column chromatography with alumina, eluting with a gradient of 0-10% EtOAc in hexane, to give 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (2.5 g, 5.82 mmol, 65.9% yield) as colorless oil. This was used as such without further purification. m/z (ESI, +ve ion) 430 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]([CH3:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.CN(C)C=O.C(Cl)Cl>[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]([CH3:25])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(N(C)c3ccc([N+](=O)[O-])cc3)c2cc1OC
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2nccc(N(C)c3ccc(N)cc3)c2cc1OC
Yield: 66.1 %

Procedure:
(6,7-Dimethoxyquinolin-4-yl)-methyl-(4-nitrophenyl)amine (0.30 g, 0.88 mmol), potassium carbonate (1.3 g, 9.4 mmol) and palladium hydroxide (1.00 g, 7.12 mmol) was hydrogenated in a mixture of ethanol (32 mL, 540 mmol), N,N-dimethylformamide (5 mL, 60 mmol) and methylene chloride (19 mL, 290 mmol) at 40 psi overnight. The mixture was filtered through Celite, and washed with calcium carbonate solution and brine then dried over sodium sulfate and concentrated to yield a crude product. This material was purified by prep. HPLC to yield [N-(6,7-Dimethoxy-quinolin-4-yl)-N-methyl-benzene-1,4-diamine (0.180 g, 66%). LCMS m/z=310 (M+1).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1C)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[CH:10]12[CH2:14][CH:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:40][CH2:39][CH2:38][C:33]3[CH:34]=[C:35]([F:37])[CH:36]=[C:31]([F:30])[CH:32]=3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Product: Fc1cc(F)cc(CCNc2nccc(-c3cccc(CN4CC5CC4CN5)c3)n2)c1

Procedure:
Intermediate 142 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 422. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.78 (s, 1H) 8.38 (d, 2H) 8.00 (d, 1H) 7.77 (t, 1H) 7.68 (d, 1H) 7.00 (d, 2H) 6.75 (t, 1H) 4.84 (d, 1H) 4.65 (s, 2H) 4.60 (d, 1H) 4.24 (d, 1H) 4.10 (d, 1H) 3.89 (d, 1H) 3.68 (d, 1H) 3.63 (t, 2H) 3.07 (t, 2H) 2.86 (d, 1H) 2.37 (d, 1H).
Reaction SMILES: S(O[CH:6]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)(=O)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]3([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:36](=[O:43])[NH:35][CH2:34]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(OC(C)C)(C)C>O.CN(C)C=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH2:8][CH2:7][CH:6]([N:40]3[CH2:39][CH2:38][C:37]4([N:33]([C:30]5[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=5)[CH2:34][NH:35][C:36]4=[O:43])[CH2:42][CH2:41]3)[CH2:11][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)OC1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccc(F)cc2)C12CCN(C1CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Reaction time: 50 h

Procedure:
A mixture of 16 g of 4,4-bis(p-fluorophenyl)cyclohexyl mesylate, 10 g of 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 234°-234.5° C), 6.1 g of potassium carbonate, 7.3 g of potassium iodide and 100 ml of dimethylformamide is stirred at 70°-80° C for 50 hours. The reaction mixture is poured into water, isopropyl ether is added to the aqueous mixture, and the resulting mixture is stirred for some time. The precipitated crystals are collected by filtration and dissolved in a mixture of chloroform and methanol (9:1). The solvent is removed to some degree and cooled in an ice bath. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 237°-240° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][O:22][CH2:21]1>C1COCC1>[CH2:1]([O:8][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:24]([CH2:23][O:22][CH2:21][C:20]([OH:27])=[O:26])=[O:25])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCCNC(=O)OCc1ccccc1
Reactant: O=C1COCC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)COCC(=O)NCCCCCCCNC(=O)OCc1ccccc1
Yield: 85.2 %

Procedure:
To the solution of 21 (350 mg, 1.324 mmol) in THF (4 mL) was added diglycolic anhydride (161 mg, 1.39 mmol) in one portion. The resultant mixture was stirred at ambient temperature for 12 h. After removed THF under reduced pressure, the residue was crystallized by EtOAc/hexane to give 429 mg white solid as first crop, in 85% yield. 1H NMR (400 MHz, DMSO-d6): δ12.79 (brs, 1H), 7.81 (t, J=5.52 Hz, 1H), 7.34-7.29 (m, 5H), 7.21 (t, J=5.46 Hz, 1H), 5.00 (s, 2H), 4.10 (s, 2H), 3.94 (s, 2H), 3.08 (q, J=6.56 Hz, 2H), 2.97 (q, J=6.28 Hz, 2H), 1.42-1.37 (m, 4H), 1.24 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 171.43, 168.53, 156.06, 137.30, 128.27, 127.65, 70.18, 67.88, 65.04, 40.22, 38.08, 29.65, 29.00, 28.38, 26.28, 26.14. mp 74-74.5° C. IR v (Diamond, cm−1): 3374, 3331, 1726, 1688, 1608, 1548, 1249, 1236, 1135, 956, 701. MS (ESI) m/z found 381.4 (M+H)+.
Reaction SMILES: [C:1]([S:5][CH2:6][CH:7]([CH3:11])[C:8](O)=[O:9])(=[O:4])[CH2:2][CH3:3].S(Cl)([Cl:14])=O>>[C:1]([S:5][CH2:6][CH:7]([CH3:11])[C:8]([Cl:14])=[O:9])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)SCC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(=O)SCC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-propanoylthio-2-methylpropanoic acid (19.7 g) and thionyl chloride (16 g) was stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure to give the title compound, b.p. 135°-137° C. (35 mmHg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[CH:29][CH:28]=4)=[O:32])=[CH:40][CH:39]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)[nH]c2c1

Procedure:
Compound 637 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethyloxy)-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C27H28N4O4: 473.21; found: 473.08.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:26](=[CH:27][CH:28]=1)[C:12]1[NH:13][C:14]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([Cl:29])=[CH:6][C:5]2=1.[CH3:30][C:31]([OH:35])([C:33]#[CH:34])[CH3:32].C(NC(C)C)(C)C.O>CN(C=O)C.C(OCC)(=O)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)I>[Cl:29][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:11]1[NH:15][C:14]([C:16]3[C:17]([C:18]#[N:19])=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]#[N:25])=[N:13][C:12]=1[C:26]1[CH:27]=[CH:28][C:2]([C:34]#[C:33][C:31]([OH:35])([CH3:32])[CH3:30])=[CH:3][C:4]2=1
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccc(Cl)cc3c3cc(Br)ccc3c2[nH]1
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)C#Cc1ccc2c(c1)c1cc(Cl)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 13 g of 2-(9-bromo-6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile in 240 mL of DMF is added 5.5 mL of 2-methyl-3-butyn-2-ol, 2.0 g of tetrakis(triphenylphosphine)palladium, 1.1 g of copper iodide and 5.6 mL of diisopropylamine. The mixture is stirred at 55° C. for 1 hr then cooled to room temperature and diluted with ethyl acetate (250 mL). Water (250 mL) is added and the layers were separated, the organic phase is washed with brine, dried over magnesium sulphate and volatiles are removed under reduced pressure. The crude mixture is then purified on silica gel using 50% hexane/ethyl acetate. The product is then recrystallized in THF and triturated in hot ethyl acetate/ether mixture to afford 5.4 g of [9-chloro-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile as a light yellow solid. 1H NMR (Acetone-d6): 8.93 (s, 2H), 8.53 (m, 2H), 8.36 (d, 2H), 8.01 (t, 1H), 7.78 (d, 2H), 4.53 (s, 1H), 1.61 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:21]=[CH:20][C:9]([CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[OH:19])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH3:22]I.O>CN(C=O)C>[CH:3]([C:6]1[CH:21]=[CH:20][C:9]([CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[O:19][CH3:22])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixed solution of sodium hydride (a 60% liquid paraffin dispersion, 757 mg, 18.9 mmol) in DMF (50 mL) was added dropwise 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in Reference Example 148 (4.01 g, 15.8 mmol) in DMF (15 mL) under argon atmosphere at 0° C., and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of methyl iodide (2.69 mL, 18.9 mmol) in DMF (8 mL) at the same temperature, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain 3.49 g (yield 82%) of the title compound. Oily matter.
Reaction SMILES: Cl.[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([CH2:30][C:31](O)=[O:32])[N:28]=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1>ClCCl>[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:31](=[O:32])[CH2:30][N:29]5[C:25]([CH3:24])=[CH:26][C:27]([C:34]([F:37])([F:36])[F:35])=[N:28]5)[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: c1ccc(C2CC(c3csc(N4CCNCC4)n3)=NO2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperazine hydrochloride (i.e. the product of Example 7, Step E) (200 mg, 0.57 mmol) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.120 g, 0.57 mmol) in dichloromethane (10 mL) at room temperature was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.110 g, 0.57 mmol), triethylamine (0.086 g, 0.85 mmol) and 1-hydroxy-benzotriazole hydrate (0.020 g, 0.14 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography using 3% methanol in chloroform as eluant to give 180 mg of the title product, a compound of the present invention as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4]>Cl>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N2CCN(C)CC2)cc1
Agent: Cl
Product: CC(C(=O)O)c1ccc(N2CCN(C)CC2)cc1
Yield: 68.5 %

Procedure:
A solution of diethyl 2-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)malonate (3.50 g, 10.0 mmol) in conc. HCl (20 ml) was stirred for 18 h at reflux in a sealed tube. The reaction mixture was concentrated and co-distilled with toluene to afford (1.7 g, 70%) of 2-(4-(4-methylpiperazin-1-yl)phenyl)propanoic acid as dark brown solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12](O)[CH2:11][CH:10]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[OH-].[Na+]>CCOCC.CN(C=O)C>[Cl:3][CH:12]1[C:13]2[C:9](=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11]1
Reactant: OC1CC(c2ccc(F)cc2)c2cc(Cl)ccc21
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1ccc(C2CC(Cl)c3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionylchloride (44 ml) was added dropwise with water-cooling to a solution of 5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-ol in ether (2L) with a catalytic amount of DMF (0.5 ml). Then the mixture was stirred for 2 hours at room temperature, poured into ice and neutralized with 9N NaOH. The organic phase was separated, dried (MgSO4) and evaporated to give 140 g of crude 1,5-dichloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:6][N:7]=1.CN(C=O)C.[Br:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:26][CH2:25][Br:24])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(O)c2)cnc1N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(OCCBr)c2)cnc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
3-Amino-6-(3-hydroxyphenyl)-N-methylpyrazine-2-carboxamide (1.01 g, 4.1 mmol) was taken into DMF (10 mL) followed by addition of 1,2-dibromoethane (10 mL) and cesium carbonate (2.7 g, 8.2 mmol). The mixture was warmed to 85° C. over 5 days followed by addition of another aliquot of cesium carbonate and 1,2-dibromoethane and heating was continued an additional 4 hours. The mixture was diluted with an excess of ethyl acetate and washed with water (3×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration ill vacuo followed by purification of the residue using silica gel flash chromatography using ethyl acetate:hexanes (1:1) as eluent. The pure fractions were combined and concentrated then dried in vacuo to give 3-amino-6-{3-[(2-bromoethyl)oxy]phenyl)-N-methylpyrazine-2-carboxamide (486 mg, 34% yield) was a yellow solid: MS (EI) for C14H16N4O2Br: 351, 353 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH:25]1([N:28]2[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:34]([CH:31]3[CH2:30][CH2:29][N:28]([CH:25]4[CH2:26][CH2:27]4)[CH2:33][CH2:32]3)=[O:35])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCN(C2CC2)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C3CC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-cyclopropyl-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a white foam. MS m/e: 500.3 [M]+.