Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(NNC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2nc(-c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)[nH]c2=O)cc1

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-methoxyphenyl)hydrazinecarboxylate (Intermediate-55, 0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.018 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 3.82 (s, 3H), 4.46 (d, J=5.8 Hz, 2H), 6.12 (m, 1H), 6.95 (d, J=8.9 Hz, 2H), 7.26-7.30 (m, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.82 (d, J=8.9 Hz, 2H), 11.01 (br s, 1H); MS (m/z): 433.20 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][O:12][CH2:11]1.O>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:14](=[O:15])[CH2:13][O:12][CH2:11][C:10]([OH:17])=[O:16]
Reactant: O=C1COCC(=O)O1
Reactant: Cc1cccc(CN)c1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(CNC(=O)COCC(=O)O)c1
Reaction time: 1 h

Procedure:
N-(3-methylbenzyl)-diglycolic acid, monoamide was prepared as follows: 2.4 g (0.02 moles) of 3-methylbenzylamine (Aldrich Chemical) was added to 3.0 g (0.026 mole) of diglycolic anhydride (Aldrich) dissolved in 15 mL dioxane. The solution was warmed, with stirring, at 70°-80° C. for 60 min. After cooling slightly, water was added to near the cloud point. After standing 60 minutes at room temperature, the crystals were filtered by suction, washed with water, and air dried. Recrystallized from water-ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[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:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[O:65]([CH2:69][CH2:70]O)[CH2:66][CH2:67][OH:68]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:42])=[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]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:70][CH2:69][O:65][CH2:66][CH2:67][OH:68])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCCOCCO
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)OCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150 mg, 0.243 mmol) in methylene chloride (8 mL) was added triethylamine (72.0 mg, 0.10 mL, 0.717 mmol) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 92 mg, 0.365 mmol). The mixture was stirred at room temperature for 10 min before 2,2′-oxydiethanol (Aldrich, 154 mg, 0.14 mL, 1.45 mmol) was added. This reaction mixture was stirred at room temperature overnight. It was then diluted with methylene chloride and washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (eluting with hexane/ethyl acetate, 80/20 to 10/90) to give chiral 2-(2-hydroxyethoxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (40.8 mg, 23% yield). MS (ES+) m/z calcd. for C35H38Cl2F2N3O6 [(M+H)+]: 704. found: 704.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5]Cl.CN(C)[CH:14]=[O:15].Cl>C(OCC)C>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][CH:14]=[O:15]
Reactant: CN(C)C=O
Reactant: ClCc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=CCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
A 200-mL three-necked flask equipped with a thermometer, a dropping funnel, a three-way stopcock, and a mechanical stirrer was purged with nitrogen. Thereto, were added 1.85 g (76 mmol) of magnesium, and 30 mL of diethyl ether. The dropping funnel was filled with a solution of 13.5 g (69 mmol) of 2,6-dichlorobenzyl chloride (produced by Tokyo Kasei K.K.) in 40 mL of diethyl ether. The solution was added dropwise into the flask by keeping the temperature of the reaction system at about 30° C. Thereafter, the reaction mixture was aged at room temperature for 30 minutes, and cooled with ice. Thereto, 6 g (82 mmol) of N,N-dimethylformamide was added dropwise. The reaction mixture was aged at room temperature for one hour, cooled with ice, and poured into 50 mL of 3N hydrochloric acid solution. The mixture was allowed to separate into phases, and the separated matter was extracted with diethyl ether. The combined organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, 5 mL of methyl t-butyl ether was added to the concentration residue, and the mixture was heated to dissolve the residue. After cooling of the solution to room temperature, the deposited crystalline matter was collected by filtration to obtain 8.1 g (43 mmol) of crystalline 2,6-dichlorophenylacetaldehyde. (Yield: 62%)
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:6][C:7](=[O:26])[N:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH3:2]>O1CCOCC1.O.Cl>[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:6][C:7](=[O:26])[N:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(C(=O)OC)cc2)c(CC)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(C(=O)O)cc2)c(CC)n1
Yield: 61.9 %

Procedure:
Methyl 4-[(5,7-diethyl-2-oxo-4-phenylthio-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]benzoate (200 mg) was dissolved in a mixture of dioxan (4 ml), water (1 ml) and concentrated hydrochloric acid (1 ml) and the mixture was heated at reflux for 4 hours. Volatile material was then removed by evaporation and toluene was added to the residue. Volatile material was again removed by evaporation. The solid residue was recrystallised from ethanol/ether to give 4-[(5,7-diethyl-2-oxo-4-phenylthio-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]benzoic acid (120 mg) m.p. 260°-262° C.; NMR (d6 -DMSO): 1.19(t, 3H), 1.51(t, 3H), 2.98(q, 2H), 3.72(q, 2H), 5.56(s, 2H), 5.91(s, 1H), 7.35(d, 2H), 7.47(s, 1H), 7.6-7.8(complex m, 5H), 7.88(d, 2H); mass spectrum (CI, ammonia): 445(M+H)+ ; microanalysis, found: C, 64.5; H, 5.4; N, 5.9%; C26H24N2O3S requires: C, 64.9; H, 5.2; N, 5.8%.
Reaction SMILES: O.[NH2:2]N.C[N:5](/[CH:7]=[N:8]/[C:9]([C:11]1[C:19]2[N:18]=[C:17]([CH3:20])[N:16]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:14]=[C:13]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:12]=1)=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:20][C:17]1[N:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:14]=[C:13]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:12]=[C:11]([C:9]3[N:8]=[CH:7][NH:5][N:2]=3)[C:19]=2[N:18]=1
Reactant: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Hydrazine hydrate (3 mL) was added to a solution of N-[(1E)-(dimethylamino)methylidene]-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide (130 mg, 0.29 mmol) in acetic acid (10 mL) and stirred at 130° C. for 30 min. The reaction mixture was cooled to rt and poured into saturated Na2CO3 solution (20 mL). A filtration was performed, and the filter cake was purified by silica gel chromatography eluted with EtOAc to give the product (88 mg, 72%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.50 (s, 3H), 3.09 (s, 4H), 3.71 (s, 4H), 6.06 (s, 2H), 6.37 (d, 1H, J=7.8 Hz), 7.20 (s, 1H), 7.34 (t, 1H, J=7.8 Hz), 7.54 (s, 1H), 7.61-7.72 (m, 2H,), 7.86 (d, 1H, J=8.4 Hz), 8.02 (d, 1H, J=7.8 Hz), 8.09 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 13.85 (s, 1H); LC-MS: m/e=425 [M+1]+
Reaction SMILES: C(OC(=O)[NH:5][C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][NH2:9])C.[BrH:13]>C(O)(=O)C>[BrH:13].[BrH:13].[CH3:10][C:6]([NH2:5])([CH3:11])[CH2:7][CH2:8][NH2:9]
Reactant: CCOC(=O)NC(C)(C)CCN
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(N)CCN
Yield: 55 %

Procedure:
2.8 g of ethyl(3-amino-1,1-dimethylpropyl)carbamate are cooled with an ice bath. 9.9 mL of 33% HBr in acetic acid are added dropwise and then the mixture is refluxed with heating for 2 h. After returning to RT, the product is precipitated with Et2O, and filtered. The obtained powder is dried in the oven at 70° C. 2.34 g (yield=55%) of 3-methylbutane-1,3-diamine dihydrobromide are obtained as a white powder used as such.
Reaction SMILES: C([O:8][C@H:9]1[CH2:12][C@H:11]([O:13][C:14]2[CH:45]=[CH:44][C:17]([CH2:18][C@H:19]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:20][C@@H:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:16][CH:15]=2)[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C@H:9]1[CH2:10][C@H:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][C@H:19]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:20][C@@H:21]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:44][CH:45]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O[C@H]2C[C@H](OCc3ccccc3)C2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O[C@H]2C[C@H](O)C2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
43 mg (0.07 mmol) of di-tert-butyl (4S)-4-(4-{trans-[3-(benzyloxy)cyclobutyl]oxy}benzyl)-N-(tert-butoxycarbonyl)-L-glutamate were dissolved in 10 mL of methanol and under argon atmosphere palladium (10% on charcoal) was added and the suspension hydrogenated overnight at room temperature. The reaction mixture was filtered, the solvent evaporated and the residue was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([N:36]4[CH2:37][CH2:38][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35]4)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c4)cc3N2)cc1OC
Yield: 51.8 %

Procedure:
Example ER-896388 was prepared in two steps from 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (25 mg, 0.056 mmol) and commercially available tert-butyl piperazine-1-carboxylate (42 mg, 0.224 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 4-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)piperazine-1-carboxylate (18 mg, 0.029 mmol, 52% yield). Then, this intermediate (16 mg, 0.026 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-896388 (14 mg, 98% yield).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH2:31][O:32][CH3:33])[NH:15][C:14]2=[O:34])=O)=CC=1)([O-])=O.[C:35]1([C:41]2([C:51]3[O:52][CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[N:13]([C:11](=[O:10])[NH:50][CH2:49][CH2:48][CH2:47][N:44]2[CH2:45][CH2:46][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:51]3[O:52][CH:53]=[CH:54][CH:55]=3)[CH2:42][CH2:43]2)[C:14](=[O:34])[NH:15][C:16]=1[CH2:31][O:32][CH3:33])=[O:28]
Reactant: NCCCN1CCC(c2ccccc2)(c2ccco2)CC1
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3ccccc3)(c3ccco3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (20 mg, 0.04 mmol) in 2 ml of CH2Cl2 was added 3-(4-phenyl-4-furan-2-yl-piperidin-1-yl)-propylamine (12 mg, 0.04 mmol) and resulting solution was stirred for 2 h at 25° C. The reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel (5% MeOH/CHCl3) to yield 22 mg (85%) of the desired product, which was converted to HCl salt and recrystallized from EtOAC-Et2O to afford 18 mg of the product as a white solid: mp 153-155° C.; Anal. Calc. For C33H36F2N4O6 requires C, 60.1; H, 5.46; N, 8.49. Found: C, 58.9; H, 5.53; 8.45.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1>[C:2]1([C:15]2[C:14]([C:17]3[C:22]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=[CH:11][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(Br)cc1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccccc2-c2ccccc2-c2ccccc2)cc1

Procedure:
The reaction is carried out as in Example 9 except that the 18.7 parts of 4-bromoanisole are replaced by 23.3 parts of 4-bromobiphenyl, and 110 parts of xylene are added as a solvent. After the reflux period, the reaction mixture is not steam distilled, but is cooled, and the solids present are collected by filtration, and washed on the filter with water and with 200 parts of toluene. The filter cake is dried, transferred to a Soxhlet extractor and continuously extracted for 96 hours with 100 parts of boiling dimethyl formamide. Quaterphenyl crystallises when the dimethyl formamide is cooled, and is collected and dried. 7.3 parts of quaterphenyl, m.p. 313°-317° are thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CO)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Reaction time: 1.25 h
Yield: 99.8 %

Procedure:
To a bi-phasic mixture of Intermediate 29b (737 mg, 3.00 mmol) in EtOAc (22.5 mL) and 1N NaOH solution (8.11 mL, 8.11 mmol) at 0° C. was added 2,2,2-trichloroethyl chloroformate (0.45 mL, 3.30 mmol) and the mixture stirred for 1.25 h. The layers were separated and the organic layer was washed with brine, dried and concentrated in vacuo to give the title compound as an off-white solid (1.26 g, 99%). LCMS (Method 3): Rt 4.00 min, m/z 420, 422 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)[O:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=4)[CH:16]=3)[O:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of ethyl 4-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)chromen-6-yl]-ethynyl]-benzoate (Compound 266, 90.0 mg, 0.213 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 70.0 mg (83%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.57 (2H, d, J=8.3 Hz), 7.40 (1H, dd, J=2.1, 8.3 Hz), 7.30-7.20 (4H, m), 7.16 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=8.3 Hz), 5.67 (1H, s), 2.38 (3H, s), 1.49 (6H, s).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]([CH3:19])([CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.C(O)C.NN>[Ni]>[NH2:6][C:7]([CH3:19])([CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(C)(N)Cc1ccc(N)cc1
Temperature: 40 °C
Reaction time: 0.02 h

Procedure:
2-Amino-2-methyl-1-(4-nitrophenyl)propane sulfate (6.07 g, 25 mmol) was suspended in ethanol (33 ml, 50 mmol) was added with stirring. Hydrazine (2.5 g, 78 mmol) was added, followed by Raney nickel (0.2 ml of 50% slurry). After 1 min gas evolution began, and the mixture turned yellow and was warmed to about 40° C. After 20 min gas evolution has almost ceased. Fresh catalyst was added and the mixture was boiled with stirring for 5 min to decompose excess hydrazine. After cooling, the suspension was filtered, the catalyst was washed with ethanol, and the filtrates were evaporated. The residue was extracted with diethyl ether (3×40 ml), and the extracts were dried (K2CO3) and evaporated, leaving a yellow oil, which solidified (3.87 g); mp 82-84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH:13]([C:15]2([CH2:18][CH3:19])[CH2:17][CH2:16]2)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:21].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:18]([C:15](=[CH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:16][CH2:17][Br:21])[CH3:19]
Reactant: CCC1(C(O)CCc2ccc(OC)c(OC)c2)CC1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CCC(=CCCc1ccc(OC)c(OC)c1)CCBr

Procedure:
3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 16 g. of 2-(3,4-dimethoxyphenyl)ethyl 1-ethylcyclopropyl carbinol (Preparation B4), 16.8 g. of phosphorus tribromide, 16.8 g. of lithium bromide and 17.6 g. of zinc bromide according to the procedure given above in Preparation C1. The product was used directly in the succeeding step (Preparation D4) without isolation.
Reaction SMILES: C1CCCCC1.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:13](=O)[CH2:14][CH:15]([CH3:17])[CH3:16]>O>[CH3:16][CH:15]([CH3:17])[CH:14]=[CH:13][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: CC(C)CC=O
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)C=CN1CCOCC1
Temperature: 50 °C

Procedure:
Into a 12 liter flask equipped with stirrer, Bidwell trap, thermometer, heating mantle, addition funnel and condenser is placed 2,200 ml of cyclohexane and 2,180 grams (25 moles) of morpholine. The resulting mixture is heated to 50° C. and 2,155 grams of isovaleraldehyde are added over a 1.5 hour period. An exotherm occurs and the solution begins to reflux. Additional heat is applied and the refluxing is continued until no additional water is collected in the Bidwell trap. The cyclohexane is then stripped off and the reaction product is distilled through a 1" stone packed column at total take-off yielding the following fractions:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C:7]1([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:4].CCN(CC)CC.[CH:28]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH2:30][CH2:29]1>C(Cl)Cl>[CH:28]1([CH2:31][S:32]([N:16]2[CH2:17][CH2:18][N:13]([C:7]3([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:19])([F:1])[F:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:14][CH2:15]2)(=[O:34])=[O:33])[CH2:30][CH2:29]1
Reactant: O=S(=O)(Cl)CC1CC1
Reactant: O=C(NCC1(N2CCNCC2)CCCCC1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1(N2CCN(S(=O)(=O)CC3CC3)CC2)CCCCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring ice-cold solution of 14 (10.0 g, 34.09 mmol) and Et3N (14.2 mL, 102.27 mmol) in CH2Cl2 (200 mL) was slowly added 1-cyclopropylmethylsulfonyl chloride (5.27 g, 34.09 mmol). The mixture stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was washed with 2 N NaOH (50 mL), 2 N HCl (50 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford N-((1-(4-(cyclopropylmethylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,2,2-trifluoroacetamide (18) as an off-white solid (14.00 g, quantitative): MS (ESI+) m/z 412.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccncc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccncc1
Yield: 93 %

Procedure:
3-(4-Pyridyl)acrylic acid (16.18 g, 0.1085 mol) was slurried in 200 ml of absolute ethanol. Concentrated sulfuric acid (8 ml) was added and the reaction was refluxed for 3 hours. After cooling, the solvent was evaporated and the residue was cautiously neutralized with saturated sodium bicarbonate solution. The resulting mixture was then extracted twice with diethyl ether. The organic extracts were washed with water and then brine, dried over MgSO4 and concentrated to afford 17.88 g (93% yield) of the subtitle compound.