Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N+:13]([CH3:16])([O-:15])=[O:14].C[O-].[Na+]>CO>[OH:1][C:2]1([CH2:16][N+:13]([O-:15])=[O:14])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred and cooled mixture of ethyl 4-oxo-1-piperidinecarboxylate (85.5 g), nitromethane (33.6 g) in methanol (240 ml), sodium methoxide (10 g) is added dropwise. Upon completion, stirring is continued for 2 hours at about 10° C. and further overnight at room temperature. The reaction mixture is evaporated at room temperature, crushed ice is added to the oily residue and the whole is acidified with acetic acid. The product is extracted with trichloromethane, the extract is dried, filtered and evaporated. The oily residue solidifies on triturating in petroleumether. The product is filtered off and dried, yielding 73 g of ethyl 4-hydroxy-4-(nitromethyl)-1-piperidinecarboxylate (interm. 5).
Reaction SMILES: N#N.[I:3][CH:4]1[CH:9]2[O:10][C:11](=[O:12])[CH:7]3[CH:8]2[C:13]2([CH2:15][CH2:14]2)[CH:5]1[CH:6]3[C:16]([OH:18])=[O:17].[CH3:19][Si](C=[N+]=[N-])(C)C>CO>[I:3][CH:4]1[CH:9]2[O:10][C:11](=[O:12])[CH:7]3[CH:8]2[C:13]2([CH2:15][CH2:14]2)[CH:5]1[CH:6]3[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=C(O)C1C2C(=O)OC3C(I)C1C1(CC1)C32
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CO
Product: COC(=O)C1C2C(=O)OC3C(I)C1C1(CC1)C32
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 6-iodo-2-oxohexahydrospiro[3,5-methanocyclopenta[b]furan-4,1-cyclopropane]-7-carboxylic acid (5.00 g, 14.96 mmol) in dry MeOH (75 mL) was added TMSCH2N2 (2.0 M in hexanes, 37.0 mL, 74.83 mmol). The reaction mixture was stirred at rt overnight, concentrated under reduced pressure and purified by FC (hept/EA, 4:1) to give the title compound as a white solid. TLC: rf (hept/EA, 4:1)=0.18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)=[CH:23][CH:24]=5)[NH:19][CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.[H-].[Na+].Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:38]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)=[CH:23][CH:24]=5)[N:19]([C:37]([O:39][C:40]5[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=5)=[O:38])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccn2c1CSC2c1cccnc1)c1cn(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a solution of 3-(pyridin-3-yl)-7-(6-phenylmethoxyindol-3-yl)carbonyl-1H,3H-pyrrolo[1,2-c]thiazole (200 mg, 0.443 mmol), prepared as in Example 4, in DMF (12 mL) was added NaH (60% oil dispersion, 19 mg, 0.465 mmol) and the reaction mixture was stirred for 7 min at ambient temperature. 4-nitrophenyl chloroformate (94 mg, 0.45 mmol) was added and the amber solution was stirred for two hours at ambient temperature. The reaction mixture was partitioned between H2O and ethyl acetate. The organic phase was dried over MgSO4, filtered,and concentrated. The title compound (98 mg), was purified by flash chromatography on silica gel (60 g, 1:1 ethyl acetate, hexanes).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13](=[O:23])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH3:12])[CH:5]=1.CO.[OH-].[Na+].Cl>O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:13]([C@@H:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:24])=[O:2])[CH3:12])=[O:23])=[CH:20][CH:19]=1)#[N:22]
Reactant: COC(=O)c1cccc(O[C@@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](Oc1cccc(C(=O)O)c1)C(=O)Nc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Heat a suspension of 3-[(S)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid methyl ester (0.42 g, 1.30 mmol) in a 1:1 mixture of MeOH:water (10 mL) to 50° C. and add sodium hydroxide (1.0 mL, 2.5 mmol) as a 10% aqueous solution. Stir the mixture at 50° C. for 1 h during which time all of the solids dissolve. Cool the reaction mixture to room temperature and adjust the pH of the mixture to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. Dilute the mixture with water and extract with methylene chloride. Dry the combined organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to provide 0.38 g of 3-[(S)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid as a foam.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2cc(F)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 80.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 45 (61 mg, yield 80.8%) as an orange solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:4]=2[N:5]=[C:6]([CH2:8][CH3:9])[N:7]=1.[NH2:15][CH2:16][CH:17]([OH:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][N:12]1[C:3]2[C:2]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[N:7][C:6]([CH2:8][CH3:9])=[N:5][C:4]=2[C:10]([CH3:14])=[N:11]1
Reactant: CC(O)CN
Reactant: CCc1nc(Cl)c2c(n1)c(C)nn2C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(NCC(C)O)c2c(n1)c(C)nn2C
Temperature: 25 °C
Reaction time: 60 h
Yield: 76 %

Procedure:
A mixture of 10.5 g (0.05 mol) of 7-chloro-5-ethyl 1,3-dimethylpyrazolo[4,3-d]pyrimidine (Ex. 11) 7.5 g (0.1 mol) of 1-amino-2-propanol and 8 ml of triethylamine in 75 ml of methylene dichloride is stirred at room temperature for 60 hours and filtered. The hygroscopic solid is stirred in 50 ml of saturated sodium bicarbonate solution to give 9.5 g (76%) of 1-[1,3-dimethyl-5-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]amino-2-propanol, a hemihydrate melting at 116°-119° C. from ethyl acetate-pet ether.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[N:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:24]=[O:25].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:24]([NH:23][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:25])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CN=C=O
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
A suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (3.2 g.), methyl 2-isocyanatoacetate (1.4 g.) and triethylamine (1.2 g.) in acetonitrile (50 cc.) is stirred for 18 hours at a temperature of about 20° C. A further amount of methyl 2-isocyanatoacetate (0.7 g.) is added and stirring is continued for a further 3 hours. The precipitate is filtered off and is dissolved in methylene chloride (35 cc.). Decolourising charcoal (0.5 g.) is added. After filtration, diisopropyl ether (105 cc.) is added to the filtrate. The crystalline precipitate which forms is filtered off, washed with diisopropyl ether (15 cc.) and then dried to give 2-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxycarbonylmethylaminocarbonyloxy-isoindolin-1-one (2.5 g.) melting at 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=C[CH:41]=[CH:40][C:39]=1C.C(N)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:38][CH2:39][CH2:40][CH3:41])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCN
Solvent: ClCCl
Product: CCCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (12 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, propylamine (10 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-propylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (18 mg, 33%) as a white solid: ESI-LRMS m/e calcd for C24H33ClN4O4S [M+] 508.2, found 509.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.84 (t, J=7.4 Hz, 3H, CH3), 1.07-1.22 (m, 2H, CH2), 1.36-1.96 (m, 10H, 5×CH2), 2.18-2.30 (m, 1H, CH), 2.62 (t, J=6.4 Hz, 2H, COCH2), 3.11-3.19 (m, 2H, CONCH2), 3.27 (s, 3H, SO2CH3), 3.56 (t, J=7.6 Hz, 1H, CH), 4.30 (t, J=6.4 Hz, 2H, NCH2), 5.49 (br.t., 1H, NH), 6.58 (d, J=2.3 Hz, 1H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.93 (s, 1H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: S(=O)(=O)=O.[BrH:5].Br.[CH3:7][C:8]1[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[N:10][CH:11]=[CH:12][CH:13]=1.Br>FC(Cl)(F)C(Cl)(Cl)F.ClCCl>[Br:5][C:12]1[CH:13]=[C:8]([CH3:7])[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[N:10][CH:11]=1
Reactant: Cc1cccnc1CCCCN
Reactant: Br
Agent: O=S(=O)=O
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Br)cnc1CCCCN
Yield: 51.5 %

Procedure:
A solution of sulphur trioxide (150 ml) in 1,1,2-trifluorotrichloroethane (350 ml) was added over ca 30 min. to a suspension of 4-(3-methyl-2-pyridyl)butylamine dihydrobromide (17 g) [prepared by passing hydrogen bromide gas through a solution of the amine in dichloromethane] in 1,1,2-trifluorotrichloroethane (100 ml) and the mixture was heated under reflux for ca 16 hr. The solvent was removed by distillation and unbrominated starting material was removed by acetylation as described in Example 1(b) to yield 4-(5-bromo-3-methyl-2-pyridyl)-butylamine (6.53 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl.[N:9](OCC)=[O:10]>CCO>[N:5]1[CH:6]=[CH:7][C:2]([CH:1]=[N:9][OH:10])=[N:3][CH:4]=1
Reactant: CCON=O
Reactant: Cc1ccncn1
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccncn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
9.14 g (97.11 mmol) of 4-methylpyrimidine was slowly added to a 0° C. solution of 8.75 g HCl in 40 ml EtOH. To this white suspension was added, over 5 min, 61 ml of a 10-20% by weight solution of ethyl nitrite in EtOH. The reaction was stirred at 0° C. for 10 min and then at RT for 2.5 h. The white salt was filtered and dried under vacuum. The salt was dissolved into 20 ml H2O and very slowly treated with about 200 ml saturated aqueous KHCO3. A white solid precipitated out of the purple solution. The solid was filtered and dried under vacuum to yield the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1.[OH-].[Li+]>O.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1
Reactant: COC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2

Procedure:
Methyl 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate 10 was treated with lithium hydroxide in water and tetrahydrofuran (THF) to give 11.
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7]1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.Br[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[C:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)n1c2ccccc2c(=O)n1C(c1ccccc1)c1ccccc1
Yield: 37.6 %

Procedure:
A mixture of 1,2-dihydro-1-carboethoxy-3H-indazol-3-one (G. Heller and P. Jacobsohn, Chem. Ber, 1921, 54B, 1107; 2.06 g), triethylamine (1.01 g) and bromodiphenylmethane (2.5 g) in chloroform (60 ml) was heated under reflux for 4 hours. The reaction mixture was then washed successively with water, M hydrochloric acid and then with water, dried (MgSO4) and evaporated. The residue was dissolved in methylene chloride and purified by column chromatography using an increasing gradient of ether in methylene chloride as eluant to give (from the later fractions) 1,2-dihydro-1-carboethoxy-2-diphenylmethyl-3H-indazol-3-one as a solid (1.4 g), m.p. 115-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:35][C:36]3[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=3)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To the suspension of 0.5 g (1.24 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (Ex. 22, int. c) in 3 ml dichloromethane 0.01 ml (0.12 mmol) N,N-dimethylformamide, 0.13 ml (1.54 mmol) oxalylchloride were added dropwise under gas evolution. The resulting clear, light yellow solution was stirred for 1 h at room temperature, then evaporated to dryness, treated twice with 5 ml of dichloromethane and again evaporated to dryness. The light yellow solid was dissolved in 8 ml of dichloromethane and added dropwise to a stirred mixture of 0.13 g (1.24 mmol) 4-aminobenzonitrile and 0.46 ml (3.31 mmol) triethylamine in dichloromethane. After stirring for 3.75 h the clear yellow solution was poured on water and extracted twice with dichloromethane. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered and after addition of silica gel evaporated to dryness. Purification by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane to heptan/ethyl acetate (1:0 to 1:1 v/v) yielded 0.45 g (81%) of the title compound as a light brown solid. MS (ES−): M−H: 571.2.
Reaction SMILES: [N+]([CH:4]([CH3:6])[CH3:5])([O-])=O.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[C:21](\[C:29]#[N:30])/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=1>CCO.CCOC(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:21]([C:29]#[N:30])([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:4]2([CH3:6])[CH3:5])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)/C(C#N)=C/c1ccc(Br)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(C#N)C(c2ccc(Br)cc2)C1(C)C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Following a procedure described in Tetrahedron Lett. 1985, 1923, a mixture of 2-nitropropane (1 eq), K2CO3 (1 eq) and ester from step 1 (1 eq) in EtOH (1.2M) was stirred at 100° C. in a close bottle for 3 h. The mixture was cooled to rt, diluted with EtOAc, washed with a NH4Cl sol., brine, dried over MgSO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 95:5) afforded the title compound as oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:7](=[O:13])[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:29]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:29][C:8]1[C:7](=[O:13])[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH2:11][CH3:12]
Reactant: CCCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 4′-[(2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.67 g) in acetic acid (20 mL) was added bromine (0.46 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.26 g, 62%) as a colorless solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:26]2[C:25]3[C:20](=[CH:21][C:22]([OH:27])=[CH:23][CH:24]=3)[NH:19][C:18]=2[C:17]([C:28]([NH2:30])=[O:29])=[CH:16][CH:15]=1>N1C=CC=CC=1.CCOC(C)=O>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:27][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[C:18](=[C:17]([C:28](=[O:29])[NH2:30])[CH:16]=[CH:15][C:14]=3[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[F:7])[NH:19][C:20]=2[CH:21]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Reaction time: 17 h
Yield: 30.8 %

Procedure:
Ethyl chloroformate (8.19 mg, 0.075 mmol) was added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 18.6 mg, 0.058 mmol) in pyridine (1 mL). After 17 h, additional ethyl chloroformate (8.19 mg, 0.075 mmol) was added. After 5 h more, additional ethyl chloroformate (0.05 mL) was added. After 15 h more, the mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (5 mL), dried and concentrated. The residue was purified by preparative HPLC to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl ethyl carbonate as a white solid (7.0 mg, 28%). 1H NMR (400 MHz, chloroform-d) δ 10.44 (1H, br. s.), 7.62 (1H, dd, J=7.92, 1.98 Hz), 7.41-7.57 (2H, m), 7.20-7.40 (4H, m), 7.16 (1H, dd, J=7.81, 1.65 Hz), 6.79-6.92 (1H, m), 6.60 (2H, br. s.), 4.34 (2H, q, J=7.26 Hz), 1.41 (3H, t, J=7.15 Hz). Mass spectrum m/z 393.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1
Reactant: COCCN
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Solvent: C1COCCO1
Product: COCCNc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
A mixture of 6-chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 17) (250 mg, 0.59 mmol) and 2-methoxyethylamine (443 mg, 5.9 mmol) in anhydrous 1,4-dioxane (5 ml) was heated at 150° C. for 40 minutes in a sealed vessel under microwave irradiation. The reaction was worked up as described in Example 54 to give the title compound (108 mg, 40%) as a cream solid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@@H:31](OS(C)(=O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Clc1ccc(Nc2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
Sodium hydride (0.36 g, 60% in oil) was added to 20 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 2.0 g of 3,4-dichlorophenyl-phenylamine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 1.5 g of 3(R)-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution, and the reaction solution was then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.13 g of light brown amorphous solid 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine 1-carboxylic acid tert-butyl ester.