Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][N:21]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[C:22](=[O:34])[N:23]2[C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[C:18]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:18]1[CH:17]=[C:16]([NH:15][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:25]=[C:24]2[C:19]=1[CH2:20][N:21]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[C:22](=[O:34])[N:23]2[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NC4CCN(C(=O)OC(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-oxopiperidine-1-carboxylate (37.9 mg, 0.19 mmol) was added to a mixture of 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (78 mg, 0.15 mmol) in 1 mL of 1,2-dichloroethane. NaBH(OAc)3 (58 mg, 0.27 mmol) was added after 45 min. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with ca 5 mL of 2.5M aqueous NaOH, extracted with (3×20 mL) of ethyl acetate, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography, eluting with 90:10 hexanes-ethyl acetate to yield tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]amino}piperidine-1-carboxylate. Mass spectrum (ESI) 721.2 (M+1).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([C:20](=[NH:24])OCC)[CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1N>CO>[NH:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:20]1[C:16]1[CH:15]=[C:14]([C:10]2([CH3:13])[CH:9]3[CH:11]2[CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]3=[O:25])[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1N
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C(=N)OCC)c1
Solvent: CO
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2nc3ccccc3[nH]2)c1
Yield: 46.3 %

Procedure:
To ethyl 3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzenecarboximidoate (Preparation 42, 0.13 g, 0.34 mmol) in methanol (4 ml) at room temperature was added 1,2-diaminobenzene (37 mg, 0.34 mmol) and the mixture was heated under reflux for 1 h and then cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and washed with 10% aqueous potassium carbonate solution (10 ml). The aqueous layer was then reextracted with dichloromethane (2×8 ml). The combined organic layers were dried (MgSO4) and then concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with hexane:ethyl acetate (1:1 and then 1:2) to give the title compound as a white foam (61 mg, 47%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:42])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:42])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butylaminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])=[C:11]([C:27]([CH3:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])[CH:10]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])=[C:11]([C:27]([CH3:32])([CH3:33])[C:28]([F:29])([F:30])[F:31])[CH:10]=1
Reactant: C[C@@H](COc1ccc(Cl)cc1C(C)(C)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)COc1ccc(Cl)cc1C(C)(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl {(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}carbamate (C49) (600 mg, 1.52 mmol) in dichloromethane (24 mL), and the reaction mixture was stirred for 30 minutes. Aqueous sodium hydroxide solution (1 M, 50 mL) was added, and the mixture was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a light amber oil, which was used without further purification. Yield: 433 mg, 1.46 mmol, 96%. LCMS m/z 296.1, 298.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=6.4 Hz, 3H), 1.67 (br s, 6H), 2.13 (br s, 2H), 3.41-3.50 (m, 1H), 3.79 (dd, half of ABX pattern, J=8.8, 7.2 Hz, 1H), 3.86 (dd, half of ABX pattern, J=8.9, 4.4 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.23 (dd, J=8.8, 2.5 Hz, 1H), 7.36-7.39 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]([C:18]([OH:20])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([Cl:15])[C:8]=2[CH2:16]Br)([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:25]CC1>C(#N)C>[C:1]([C:5]1[N:6]([C:18]([OH:20])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([Cl:15])[C:8]=2[CH:16]=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)c1cc2cc(Br)c(Cl)c(CBr)c2n1C(=O)O
Solvent: CC#N
Product: CC(C)(C)c1cc2cc(Br)c(Cl)c(C=O)c2n1C(=O)O
Temperature: 50 °C
Reaction time: 7 h
Yield: 47.6 %

Procedure:
To a mixture of tert-butyl 5-bromo-7-(bromomethyl)-6-chloro-1H-indole-1-carboxylic acid (7.2 g) and acetonitrile (50 mL) was added 4-methyl morpholine-4-oxide (2.7 g) at room temperature. The reaction mixture was stirred at 50° C. for 7 hours and then at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain tert-butyl 5-bromo-6-chloro-7-formyl 1H-indole-1-carboxylic acid (2.9 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:9]1.[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25](Cl)[N:24]=1>C(O)(C)(C)C>[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[N:9]2)[N:24]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NC(=NCC(F)(F)F)Nc1ccn(CCCCOc2cncc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
Sodium hydride (46 mg. of a 61% w/w dispersion in oil) was added to a hot solution of 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (279 mg.) in dry t-butanol (10 ml.). 2,6-Dichloropyrazine (180 mg.) was added and the mixture was stirred at room temperature for two hours, followed by evaporation in vacuo to dryness. The residue was treated with dilute aqueous 0.5N HCl (10 ml.), and then extracted with EtOAc (4×10 ml.). The combined extracts were dried (MgSO4) and evaporated. The residue was purified by preparative t.l.c. on silica gel plates using triethylamine/EtOH/EtOAc 1:1:9 v/v/v as developing solvent to give 2-chloro-6-[4-(3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazol-1-yl)butoxy]pyrazine (170 mg.; 43%) having the following n.m.r. in d6DMSO: 8.25 (s, 2H); 7.4 (d, 1H); 5.6 (d, 1H); 4.25 (t, 2H); 3.9 (m, 4H); 1.7 (br m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].N1CCCC1.[CH3:18][O:19][CH2:20][C:21](=O)[CH2:22][O:23][CH3:24]>C1(C)C=CC=CC=1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:12][C:21]([CH2:22][O:23][CH3:24])([CH2:20][O:19][CH3:18])[CH2:1][C:2](=[O:3])[C:4]=2[CH:9]=1)#[N:11]
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: COCC(=O)COC
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COCC1(COC)CC(=O)c2cc(C#N)ccc2O1

Procedure:
5-Cyano-2-hydroxyacetophenone (13.57 g) was dissolved in toluene (120 ml), and pyrrolidine (6 ml) and 1,3-dimethoxy-2-propanone (15 ml) were added. The mixture was refluxed under heating for 1 hour while removing the generated water. After cooling, the reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and brine in order, and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (ethyl acetate:hexane=2:8) to give 13.0 g of 6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-one.
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:39][CH:38]=2)[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH2:30])=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(Cl)Cl>[I:18][CH:29]1[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]([C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:42]=2)[C:24]2[C:23](=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)[CH2:30]1
Reactant: [IH2+]
Reactant: C=CC(c1ccccc1)C(c1ccc(OC)cc1)c1ccc(OC(=O)C(C)(C)C)cc1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC(I)C(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (65.8 mg, 0.177 mmol) was suspended in methylene chloride (3.4 mL), and cooled in a dry ice-acetone bath to −78° C. To this, a methylene chloride (1.8 mL) solution of 1-(4-methoxyphenyl)-2-phenyl-1-(4-pivaloyloxyphenyl)-3-butene (4, 56.0 mg, 0.135 mmol) was added, and further, boron tribromide diethyl ether complex (0.015 mL, 0.118 mmol) was added divided into 3 portions. After this, and after stirring for 1 hr at −78° C., the reaction was stopped by adding a saturated ammonium chloride solution (5 mL), and after returning to room temperature, extraction was performed three times with diethyl ether (10 mL). The organic layers were combined and washed with a saturated sodium chloride solution (10 mL), dried with anhydrous sodium sulfate, and concentrated. The residue was purified with thin layer chromatography (toluene), and the subject compound (5, 51.6 mg) was obtained as a slightly yellow oily substance (yield 71%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: OCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCO
Temperature: -20 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 85.0 g (0.904 mole) of 1,5-pentanediol and 30.3 g (0.30 mole) of triethylamine in 350 mL of dry CH2Cl2 at -20° C. was added dropwise a solution of 28.5 g (0.25 mole) of methanesulfonylchloride in 100 mL of CH2Cl2 over 2 hours under nitrogen atmosphere. The solution was stirred at 2 hours at -20° C. and then at -4° C. for 18 hours. The reaction mixture was washed with H2O, 1N HCl, H2O, then dried and evaporated. The residual oil was chromatographed on a silica gel column, eluting with EtOAc-CH2Cl2 (2:8). After combining the appropriate fractions there was obtained 25.7 g (56.5%) of 5-hydroxypentylmethylsulfonate as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(C=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 2-hydroxy-4-methoxybenzaldehyde (304 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Ni]
Product: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)c1

Procedure:
Prepared from (3′-methyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C6) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white powder (212 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[S:10][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[C:8]([C:15]([NH:17][NH2:18])=[O:16])[CH:7]=1>O.Cl>[Cl:5][C:6]1[S:10][C:9]([S:11](=[O:13])(=[O:14])[NH2:12])=[C:8]([C:15]([N:17]=[N+:18]=[N-:1])=[O:16])[CH:7]=1
Reactant: NNC(=O)c1cc(Cl)sc1S(N)(=O)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc(Cl)sc1S(N)(=O)=O
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A solution of sodium nitrite (3.0 g; 43.4 mmol) in 20 ml of water was added dropwise with stirring at 0° C. to a solution of 5-chloro-2-sulfamoylthiophene-3-carbohydrazide (10.0 g; 39.1 mmol) in 80 ml of 1M hydrochloric acid and the mixture was stirred for 15 min. The precipitate was isolated by filtration, washed with water and dried to give 9.93 g (96%) of the title compound; 1H-NMR (DMSO-d6): δ 7.55 (s, 1H), 7.97 (br. s, 2H, NH2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].CCN([CH:25]([CH3:27])[CH3:26])C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:16][CH2:15][C@@H:11]1[CH2:10][C@H:27]1[C:25]#[C:26][C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C#Cc1ccc(-c2ccnc(C(=O)OC)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C#CC#C[C@@H]3C[C@H]3CO)cc2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
To a stirring solution of compound 2.6 (1.77 g, 7.5 mmol), Pd(PPh3)2Cl2 (262 mg, 0.37 mmol), CuI (143 mg, 0.75 mmol), and DIPEA (2.9 g, 22.5 mmol) in THF (50 mL) was added compound 2.8 (1.84 g, 10.5 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 5 hr. The solvent was removed under reduced pressure, and the resulting residue was diluted with water (100 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried and concentrated under reduced pressure to give a red oil, which was purified by flash chromatography (silica gel/PE:EA 5:1˜3:1) to yield methyl 4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)picolinate (2.9, 570 mg, 23%): MS: m/z calcd for C21H17NO3 331.12. found [M+H]+ 332; 1H-NMR (DMSO-d6, 400 MHz) δ 8.77 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 4.72 (t, J=5.6 Hz, 1H), 3.91 (s, 3H), 3.44 (m, 1H), 3.24 (m, 1H), 1.45 (m, 2H), 0.88 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].ClCCl.FC(F)(F)S(O)(=O)=O>C1CCCCC1>[O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8]
Reactant: CC(=O)CCCCC(=O)O
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(=O)CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (about 90% pure, 62.4 mmol) of 6-oxoheptanoic acid were initially charged in 71.8 ml of cyclohexane, and 20.46 g (93.6 mmol) of tert-butyl 2,2,2-trichloroacetimidate and 15 ml of dichloromethane were added. At −10° C. 0.55 ml (6.24 mmol) of trifluoromethanesulfonic acid were slowly added dropwise to the solution. The resulting suspension was stirred overnight with warming to RT. The insoluble precipitate was then removed by filtration. The filtrate was washed twice with sodium bicarbonate solution and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). On standing overnight, a solid precipitated from the product obtained in this manner. This solid was removed by filtration with suction and discarded. The target product, obtained in the form of the filtrate, was not purified any further. This gave 4.51 g (36.1% of theory) of the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[O:8]C([S:11][C:3]=2[CH:2]=1)=O.[OH-].[Na+].[CH:14](I)([CH3:16])[CH3:15].Cl>>[CH:14]([S:11][C:3]1[CH:2]=[CH:1][C:6]([OH:7])=[CH:5][C:4]=1[OH:8])([CH3:16])[CH3:15]
Reactant: O=c1oc2cc(O)ccc2s1
Reactant: CC(C)I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Sc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g of tioxolone (1 eq) are added to an aqueous sodium hydroxide solution (3.5 eq) (6.7 g of sodium hydroxide in 84 ml of water) at room temperature. After complete dissolution (30 minutes), 5.5 ml of isopropyl iodide are added. After stirring for two hours at room temperature, the mixture is acidified with hydrochloric acid and then extracted with ethyl ether. The organic phases are washed, dried and evaporated. The residue is recrystallized from an alcohol/water mixture to obtain pale-yellow crystals having a melting point of: 67° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH2:16]([NH:15][C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=1)=[O:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)N(CC(=O)NCc1ccccc1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)NCc2ccccc2)c2ccccc2)c1
Yield: 47.8 %

Procedure:
The procedure is analogous to that described in Example 1, but 0.25 g of 2-(2-amino-N-phenylacetamido)-N-benzylacetamide and 0.11 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from acetonitrile, 0.17 g of N-benzyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido]acetamide melting at 204° C. is obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=[O:39])[C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:32][C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:21][C:22]=2[C:23]2[S:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=2)[CH:14]=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:41][C@@H:42]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:43][OH:44].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1COCC1>[CH2:36]([NH:35][C:33](=[O:34])[NH:32][C:20]1[N:19]=[CH:18][C:17]([C:15]2[CH:16]=[C:11]3[C:12](=[CH:13][CH:14]=2)[N:41]([C@@H:42]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:43][OH:44])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]3=[O:39])=[C:22]([C:23]2[S:24][CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[N:27]=2)[CH:21]=1)[CH3:37]
Reactant: CC(C)C[C@H](N)CO
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc(F)c(C(=O)C(=CN(C)C)C(=O)OCC)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)CC(C)C)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
Ethyl 3-(dimethylamino)-2-(5-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-2-fluorobenzoyl)acrylate (0.150 g, 0.26 mmol, Intermediate 125) and (S)-2-amino-4-methylpentan-1-ol (0.033 ml, 0.26 mmol) were taken up in THF (2 ml). The mixture was placed in an oil bath and heated to 60° C. for 2 h. Potassium carbonate (0.107 g, 0.78 mmol) was added followed by DMF (1 ml) and the mixture was stirred at 60° C. overnight. Reaction was cooled to room temperature and concentrated in vacuo. The residue was then diluted with water (0.5 mL) and cooled to 0° C. 1N HCl was added drop wise until pH˜4. A light yellow solid was collected by filtration, washed with water, and dried in vacuum oven overnight at 50° C. to give (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-4-methylpentan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.072 g, 44%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[CH:8][C:7]=1[Cl:20])[CH3:2]>CCO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[Cl:20])[CH3:2]
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)ccc1Cl
Solvent: CCO
Product: CCOC(=O)Cc1cc(O)ccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(5-Benzyloxy-2-chloro-phenyl)-acetic acid ethyl ester (1.7 g, 5.6 mmol) was dissolved in EtOH (30 mL) and degassed with N2. 5% Palladium on carbon (1 g) was added, and the reaction was purged with H2 and then stirred under an H2 balloon at 50° C. overnight. The mixture was filtered and concentrated to give the title compound.