Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2O[C:12]([CH2:15][OH:16])=[N:13][N:14]=2)[CH:5]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC([S:31](O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:31][C:12]([CH2:15][O:16][CH:23]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[N:13][N:14]=2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cccc(-c2nnc(CO)o2)c1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(-c2nnc(COC3CCCCO3)s2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(5-hydroxymethyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester (9.8 g), dihydropyrane (7.7 mL) and p-toluenesulfonic acid hydrate (0.80 g) in AcOEt (100 mL) was stirred at 20° C. for 1 h. The solution was diluted with AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:2) as eluent to give 3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (12.6 g) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][C:24]([F:23])([F:36])[F:35])[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccccc4OC(F)(F)F)c3)cnc2c1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-trifluoromethoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-2′-trifluoromethoxybiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 449 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C=Cc1ccccc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
15 gm of 2-fluorocinnamic acid was suspended into 100 ml of methanol. While maintaining the suspension at 0° C., 1.7 gm of thionyl chloride was added slowly. After the addition, the mixture was stirred for 30 minutes at 0° C. and for 4 hour at room temperature. The residue obtained by the removal of the solvent was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 17.8 gm of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: N
Product: Fc1cc(F)cc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,5-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.37 (tt, J=9.0, 2.3 Hz, 1 H), 7.65 (ddd, J=7.9, 5.0, 1.0 Hz, 1 H), 7.82-7.91 (m, 2 H), 8.56 (dt, J=7.9, 2.0 Hz, 1 H), 8.75 (dd, J=4.8, 1.6 Hz, 1 H), 9.30 (dd, J=2.0, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:36])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][CH2:30][C:31](OCC)=[O:32])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:38]=1.CO[BH-](OC)OC.[Na+].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:36])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:38]=1
Reactant: CCOC(=O)CCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Agent: CO[BH-](OC)OC
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCCCO
Yield: 48.6 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(3-ethoxycarbonylpropoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.5 g) in ethylene glycol dimethyl ether (70 ml) is added sodium trimethoxyborohydride (3.78 g), and the mixture is refluxed for 3 hours. The reaction solution is gradually poured into diluted hydrochloric acid, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-1-{6-[2-(4-hydroxybutoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (1.12 g) as white powder.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[S:12](=[O:15])([OH:14])[O-:13]>O>[C:8]([CH:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH2:6][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:11])([OH:10])=[O:9]
Reactant: O=S([O-])O
Reactant: C=CCNC(=O)/C=C\C(=O)O
Solvent: O
Product: C=CCNC(=O)CC(C(=O)O)S(=O)(=O)O

Procedure:
Allylamine reacts readily with maleic anhydride in THF to give N-allylmaleamic acid (VIII) in quantitative yield. VIII reacts with bisulfite in water to form 3-carboxy-3-sulfo-N-allyl propionamide (IX). At 160° C., (IX) cyclolyzes slowly to form N-allyl-sulfo-succinimide (X).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30](Cl)[C:31](OCC)=[O:32])=[CH:25][CH:24]=1)([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]2)(=O)C.[NH2:38][C:39](N)=[S:40].S1(CCCC1)(=O)=[O:43].Cl>O.COCCO>[OH:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]3[S:40][C:39](=[O:43])[NH:38][C:31]3=[O:32])=[CH:27][CH:28]=1)([CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:9][CH2:8]2
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(CC(C)C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Agent: Cl
Solvent: O
Solvent: COCCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(COc1ccc(CC3SC(=O)NC3=O)cc1)(CC(C)C)O2

Procedure:
1.99 g of ethyl 3-[4-(6-acetoxy-2-isobutyl-5,7,8-trimethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate, 0.42 g of thiourea and 2.1 g of sulfolane were reacted under a nitrogen stream at 125°-150° C. for 3.5 hours. At the end of this time, 15 ml of ethylene glycol monomethyl ether, 4 ml of water and 2 ml of concentrated hydrochloric acid were added and the mixture was reacted for a further 3.5 hours at 96°-98° C. The reaction mixture was then treated as described in Example 1(a) and the resulting crude product, in the form of an oil, was purified by column chromatography through silica gel, eluted with a 5:1 by volume mixture of hexane and ethyl acetate, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: O=C(Nc1ccccc1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and aniline (CAN 62-53-3) as starting materials, MS (EI) m/e: 309.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([S:11]([F:14])(=[O:13])=[O:12])=[CH2:10]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]=[CH:9][S:11]([F:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C=CS(=O)(=O)F
Solvent: CN(C)C=O
Product: O=S(=O)(F)C=CNc1ccc(Cl)cc1
Yield: 82.3 %

Procedure:
To a DMF (50 mL) solution of 4-chloroaniline (3.0 g, 23.5 mmol) was added ethenesulfonyl fluoride (3.3 mL, 30 mmol). The solution was heated at 110° C. until the 4-chloroaniline was consumed (monitored by tlc). The orange solution was diluted with 1 liter of water and the resulting oily precipitate was extracted into ether. The combined organic layers was washed with water and brine and dried (MgSO4). After the ether had been removed by distillation, the brown residue afforded the title compound (4.56 g, 81%) as yellow needles which could be crystallized from ether/hexane, mp 61°-63° C. (lit. mp 62°-63° C.; Hoechst's German Patent 1104968).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1.[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]=[O:35])[CH:25]=1.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]([C:19]2[S:18][C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][C:16]=3[CH:20]=2)[OH:35])[CH:25]=1
Reactant: COc1ccc2sccc2c1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2sc(C(O)c3cc(Br)c4ccccc4c3)cc2c1
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.48 ml, 2.36 mmol) was added dropwise to a solution of 5-methoxybenzo[b]thiophene (388 mg, 2.36 mmol) in THF (6 ml) at −78° C. and the reaction solution was stirred at the same temperature for 10 minutes. To this solution, a solution of 4-bromonaphthalene-2-carbaldehyde (530 mg, 2.25 mmol) in THF (4 ml) was added dropwise. The reaction mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (725 mg, 77%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCSCc1cnccn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCSCc1cnccn1)N[N+](=O)[O-]

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]pyrazine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro N'-[2-(2-pyrazinylmethylthio)-ethyl]guanidine. Similarly by the procedure of Example 2 (iii), there is prepared N-methyl-N'-nitro-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=1)[CH2:24][CH2:23]2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2cc(F)ccc21
Yield: 55 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 5-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 197 mg of 2-[2-(5-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[NH2:64][C:65]1[CH:70]=[CH:69][C:68]([NH:71][S:72]([CH3:75])(=[O:74])=[O:73])=[CH:67][C:66]=1[O:76][CH3:77]>>[CH3:75][S:72]([NH:71][C:68]1[CH:69]=[CH:70][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:66]([O:76][CH3:77])[CH:67]=1)(=[O:74])=[O:73]
Reactant: COc1cc(NS(C)(=O)=O)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(C)(=O)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 46.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with N-(4-amino-3-methoxyphenyl)methanesulfonamide hydrochloride (Astatech) (0.2 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-methanesulfonylamino-2-methoxy-phenyl)-amide as a yellow solid (Yield 0.16 g, 47%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].F[C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:22][C:21]1[C:16]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][CH:18]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 2.011 g, 10.98 mmol) and DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (0-15% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[C:35]([NH2:40])[N:34]=[C:33]2[C:41]([N:43]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])=[O:19])=O)(C)(C)C.CCCCCCC>ClCCl>[NH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[C:35]([NH2:40])[N:34]=[C:33]2[C:41]([N:43]1[CH2:44][C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51]1)=[O:42])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: ClCCl
Product: NCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of trifluoroacetic acid are added to 371 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl 2-tert-butoxycarbonylaminoethyl carboxylate in 4 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 2 h, 5 ml of n-heptane are added, and the mixture is evaporated to dryness in vacuo. The residue is dissolved in 500 μl of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>O.[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=C1CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1

Procedure:
1.9 Grams of 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of palladium black were dispersed in 80 ml of water and the dispersion was stirred under 2 atmospheric pressure of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered for removing the palladium black and the mother liquor was concentrated under a reduce pressure then the residue thus obtained was crystallized by adding a small amount of ethanol then crude crystals thus obtained were collected by filtration and recrystallized from ethanol to obtain 1.4 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)-propyl]-3,4-dihydrocarbostyril in colorless plate-like crystals. Melting point: 155.5°-156° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:30](=[O:31])[N:29]([CH3:32])[C:11]3[N:12]([CH3:28])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH2:20][C:21](=O)[CH2:22][O:23][CH2:24][CH3:25])=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:30](=[O:31])[N:29]([CH3:32])[C:11]3[N:12]([CH3:28])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:41]([CH2:39][CH3:40])[N:42]=[C:21]([CH2:22][O:23][CH2:24][CH3:25])[CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: CCNN
Reactant: CCOCC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Agent: O=C(O)C(=O)O
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n(CC)n1

Procedure:
The process is carried out as in Example 37 above, with compound A, 1-[3-(4-fluorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-ethoxy-butane-1,3-dione and ethylhydrazine oxalate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([CH3:22])[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([CH3:22])[CH:10]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C)c1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(CN)cc(C)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 464.2 %

Procedure:
(4-Methanesulfonylamino-3-methyl-5-vinylbenzyl)carbamic acid tert-butyl ester (85.9 mg, 0.09 mmol) was dissolved in CH2Cl2. 5˜6 drops of CF3COOH were added. The reaction mixture was stirred for 12 hr. The reaction mixture was concentrated to yield brownish syrup (100.4 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.CN(C)C(=O)C>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(c4ccccn4)CC3)cc2C2=CCCCC2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (75 mg, 0.15 mmol) (as prepared in Example 14, step (b)), K2CO3 (84 mg, 0.60 mmol), 2-fluoropyridine (27 μL, 0.30 mmol) and 0.3 mL of N,N-dimethylacetamide and stirred for 8 h at 120° C. The reaction was diluted with 3 mL of H2O and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 9 min to give 50 mg (75%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.18 (d, 1H), 8.06 (m, 1H), 8.02 (s, 1H), 7.94 (dd, 1H), 7.48 (d, 2H), 7.22 (dd, 1H), 7.12 (d, 1 H), 6.98 (t, 1H), 5.82 (m, 1H), 4.32 (m, 2H), 3.46 (m, 2H), 3.00 (m, 1H), 2.30 (m, 4H), 2.18 (m, 2H), 1.96-1.74 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H28N6O, 453.2 (M+H), found 453.2.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1(=[O:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>CN(C)C=O.CCCCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:22][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: O=C1CCc2ccccc21
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCCC
Product: C[Si](C)(C)OC1C=Cc2ccccc21

Procedure:
Trimethylsilyl chloride (5.7 g, 52.3 mmole), triethylamine (11.71 g, 116 mmole), and 1-indanone (6.22 g, 47.1 mmole) were dissolved in dimethyl formamide (25 mL) and refluxed for 17 hours. After cooling, the mixture was diluted with pentane (50 mL) and washed four times with saturated sodium bicarbonate. After backwashing the aqueous phase with pentane the organic layers were combined, washed with cold 2N HCl and cold saturated sodium bicarbonate, then dried over MgSO4. The solvent was evaporated and the residue distilled (bp 123°-125° C.).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].[S:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>>[I-:1].[CH3:35][O:34][CH:10]([CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][C:37]1[S:36][CH:40]=[CH:39][NH+:38]=1)(=[O:7])=[O:6])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCc1[nH+]ccs1)OC
Product: [I-]
Yield: 55 %

Procedure:
A solution of 240 mg (0.38 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane in 2 ml of thiazole is stirred at 50° C. overnight. After thiazole is evaporated, the residue is recrystallized from dichloromethane-acetone to give 150 mg (0.209 mM) of 2-methoxy-1-octadecylcarbamoyloxy-3-(3-thiazoliopropylsulfonylamino)propane iodide Ia2 in 55% yield.