Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+:12].[OH-].[Na+].O.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+:12]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a suspension of sodium p-hydroxybenzenesulfonate (40 g, 0.17 mole) in a solution of NaOH (9.61 g, 0.24 mole) and H2O (55 ml), a solution of benzyl chloride (27.6 g, 0.22 mole) in ethanol (35 ml) was added dropwise, and continued to stir for 5 hours under reflux. After standing at room temperature overnight, the precipitate was filtered, washed with H2O and dried to afford 35.2 g of sodium p-benzyloxybenzenesulfonate as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1.N1CCCCC1>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccc(F)cc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 5-fluoroindolin-2-one (40 mg, 0.265 mmol), 1H-indazole-6-carbaldehyde (43 mg, 0.292 mmol), piperidine (3 uL, 0.027 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. LC-MS analysis of the filtered yellow solid indicated a 9:1 mixture of geometric isomers. The mixture was resolved through prep-HPLC purification to give 11 mg, 15% of the major isomer (E) as the title compound. The minor fraction was also isolated; see Example A32. 1H NMR (400 MHz, d6-DMSO) δ 13.31 (s, 1H), 10.66 (s, 1H), 8.18 (s, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.29 (d, J=9.5 Hz, 1H), 7.10 (t, J=6.8 Hz, 1H), 6.88 (dd, J1=8.8 Hz, J2=4.7, 1H); MS ESI 280.0 [M+H]+, calcd for [C16H10FN3O+H]+ 280.09.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)cc1Cl)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2,4-dichlorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.CS([Cl:43])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][Cl:43])=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:25][CH:26]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CO)c2Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CCl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(2,4-dichloro-3-hydroxymethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (148 mg), triethylamine (0.11 ml) and anhydrous dimethylformamide (1 ml) was added a 1M solution of methanesulfonyl chloride in dimethylformamide (0.77 ml) under ice-water cooling. The mixture was stirred at ambient temperature for 4 hours and partitioned between chloroform and saturated aqueous solution of sodium hydrogen carbonate. The organic layer was isolated, dried over magnesium sulfate and evaporated in vacuo to give a brown oil. The residue was purified by preparative thin layer chromatography (chloroform-methanol) to give 1-(2,4-dichloro-3-chloromethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (120 mg) as an amorphous powder.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:26]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:32]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:33])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: O=C(O)C1CCCCC1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1CCCCC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 472.2 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([CH2:8][CH2:9]COC1C(OC)=C2C(=CC=1)N=C1NC(=O)CN1C2)C(N)=O.[CH:28]1([N:33]([CH2:56][CH2:57][OH:58])[C:34](=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[C:41](Cl)=[C:42]3[C:47](=[CH:48][CH:49]=2)[N:46]=[C:45]2[NH:50][C:51](=[O:53])[CH2:52][N:44]2[CH2:43]3)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:29]1([CH2:30][CH2:31][CH2:32][CH2:28][N:33]([CH2:56][CH2:57][OH:58])[C:34](=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:41]=[C:42]3[C:47](=[CH:48][CH:49]=2)[N:46]=[C:45]2[NH:50][C:51](=[O:53])[CH2:52][N:44]2[CH2:43]3)[CH2:9][CH2:8][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CN2Cc3c(ccc(OCCCCC(=O)N(CCO)C4CCCC4)c3Cl)N=C2N1
Reactant: COc1c(OCCCC(CCO)C(N)=O)ccc2c1CN1CC(=O)NC1=N2
Product: O=C1CN2Cc3cc(OCCCCC(=O)N(CCO)CCCCC4CCCCC4)ccc3N=C2N1

Procedure:
N-cyclohexyl-N-(2-hydroxyethyl-5-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide; N-cyclopentyl-N-(2-hydroxyethyl)-5-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][NH:4][N:3]=1.[C:16]([CH:18]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:17].N12CCCN=C1CCCCC2>C(#N)C>[C:16]([CH2:18][C:19]1([N:4]2[CH:5]=[C:6]([B:7]3[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]3)[C:2]([CH3:1])=[N:3]2)[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:17]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1nn(C2(CC#N)CN(C(=O)OC(C)(C)C)C2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 5.10 mmol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.00 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL, 2.6 mmol) in acetonitrile (20 mL) was heated at 60° C. for 2 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C16H24BN4O4 (M−55)+: m/z=347.2. Found: 347.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH4+:15].[OH-]>C1COCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[S:11](=[O:13])(=[O:12])[NH2:15]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Temperature: 0 °C

Procedure:
2-Acetamido-4-methylthiazole-5-sulfonyl chloride (0.50 g, 1.96 mmol) was dissolved in THF (7 mL), cooled to 0° C., and concentrated NH4OH (0.7 mL) was added. After 3 hours the reaction was concentrated, diluted with water, and extracted with CHCl3/methanol. The organic layer was dried over Na2SO4. Filtration and concentration gave the product that was used Example 11B.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C=O>C(O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1
Reactant: C1CCNC1
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: C=O
Solvent: CCO
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(CN2CCCC2)C1=O
Temperature: 25 °C

Procedure:
(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H) (1 g, 3.8 mmol) is added to ethanol (7 ml). Pyrrolidine (312 μl, 3.8 mmol) and aqueous formaldehyde (393 μl, 5.3 mmol) are added. The mixture is heated at reflux for 3 h. The mixture is next cooled to room temperature and concentrated in vacuo to afford (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (2-a, R1=methylpyrrolidin). Spectroscopic data as reported in Example 19.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][C:12]([O:40][CH3:41])=[C:13]([O:35][CH2:36][CH2:37][O:38][CH3:39])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:43][C:44]([NH:46][CH:47]([CH3:49])[CH3:48])=[O:45].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:47]([NH:46][C:44](=[O:45])[CH2:43][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][C:12]([O:40][CH3:41])=[C:13]([O:35][CH2:36][CH2:37][O:38][CH3:39])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:49])[CH3:48]
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(O)c3)nc2cc1OC
Reactant: CC(C)NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCC(=O)NC(C)C)c3)nc2cc1OC
Temperature: 80 °C

Procedure:
To a solution of tert-Butyl 5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.400 g, 0.72 mmol) and 2-chloro-N-isopropylacetamide (0.107 g, 0.79 mmol) in DMF (16 mL) was added K2CO3 (0.297 g, 1.44 mmol). The mixture was heated at 80° C. for 72 h. The mixture was concentrated in vacuo and taken on directly into the next step. HPLC retention time 6.76 mins.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC=CC1CC(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CC(=O)N1
Yield: 97.9 %

Procedure:
A solution of 4-(2-acetoxyvinyl)-2-azetidinone (10.0 g, 0.065 mole) in 200 ml ethyl acetate containing 100 mg of 10% Pd/C is hydrogenated on a Parr shaker at 25° C. under 40 psi hydrogen for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4-(2-acetoxyethyl)-2-azetidinone (10.0 g) as a crystalline solid. Recrystallization from ether affords white crystals: M.P. 44°-7°; ir (CHCl3) μ 5.66, 5.74; nmr (CDCl3) τ 3.44 (broad s, 1, NH), 5.82 (m, 2, CH2OCOCH3), 6.29 (m, 1, C-4H), 6.87 (1/2 AB pattern further split in four by C-4H and NH, 1, Jgem =12.8 Hz, J=4.5 H JNH =1.9 Hz, 7.38 (1/2 AB pattern further split in four by C-4H and NH, 1, Jgem =12.8 Hz, J=2.3 Hz, JNH =1.0 Hz), 7.93 and 8.02 (s on m, total 5, OCOCH3 and CH2CH2OCOCH3, respectively).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+].[C:24]([O:27][CH2:28]Br)(=[O:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH2:28][O:27][C:24](=[O:26])[CH3:25])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cncn34)C[C@H]12
Reactant: CC(=O)OCBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(c2csc3cncn23)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution-of 60.2 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1.4 ml of DMF was added 67.7 mg of acetoxymethyl bromide under the atmosphere of argon at a temperature of −30° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was diluted twice with 20 ml of ethy acetate, and washed twice with 10 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 22.1 mg of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1

Procedure:
In the next step, (±)-trans-2-phenylcyclohexanol is reacted with chloroacetyl chloride at reflux in a basic solvent such as a mixture of methylene chloride and pyridine or, more preferably, 4-dimethylaminopyridine and methylene chloride. The resulting (±)-trans-2-phenylcyclohexyl chloroacetate of the formula ##STR29## can be isolated by conventional means such as extraction followed by distillation of the organic layer.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5]([C:6]3[C:7](=[C:11](C(O)=O)[NH:12][CH:13]=3)[NH:8][CH:9]=2)=[N:4][N:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([N:3]2[C:2](=[O:1])[C:10]3[C:5]([C:6]4[C:7](=[CH:11][NH:12][CH:13]=4)[NH:8][CH:9]=3)=[N:4]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Solvent: CN(C)C=O
Product: O=c1c2c[nH]c3c[nH]cc3c-2nn1-c1ccccc1
Temperature: 220 °C

Procedure:
3-Oxo-2-phenyl-2,3,5,7-tetrahydropyrazolo[3,4-d]pyrrolo[3,4-b]pyridine-6-carboxylic acid was dissolved in DMF (0.3 M) and heated at 220° C. in a microwave for 20 minutes. The crude reaction mixture was concentrated and column chromatography afforded the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (t, J=4.4 Hz, 1H) 7.14 (s, 1H) 7.36 (t, J=4.4 Hz, 2H) 7.44 (s, 1H) (8.15 (d, J=7.6 Hz, 1H) 8.29 (d, J=6.4 Hz 1H) 12.06 (s, 1H) 12.34 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Li]CCCC.CN([CH:23]=[O:24])C.[NH4+].[Cl-]>CCOCC>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[CH:23]=[O:24]
Reactant: Brc1ccc2sc3ccccc3c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=Cc1ccc2sc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) suspension of commercially available 2-bromodibenzo[b,d]thiophene (500 mg; 1.90 mmol) in anh. Et2O (5 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.26 ml; 2.01 mmol). The resulting suspension was further stirred at 0° C. for 30 min. Anh. DMF (0.156 ml; 2.03 mmol) was then added, and the mixture was stirred at rt for 20 min. Aq. sat. NH4Cl and Et2O were successively added, and the aq. layer was further extracted with Et2O. The mixed organic layers were washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded dibenzo[b,d]thiophene-2-carbaldehyde as an off-white solid. LC-MS (conditions A): tR=0.87 min.; no ionisation.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(N[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:23][C:22]([F:25])([F:24])[S:19]([O:11][C:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH:9]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: 25 °C

Procedure:
A −78° C. solution of 4-tert-butylcyclohexanone (1.54 g, 10 mmol) and N-phenyl(trifluoromethanesulfonamide) (3.75 g, 10.5 mmol) in THF (20 mmol) was treated with 1M NaHMDS in THF (11 mL), warmed to room temperature, filtered through a pad of silica gel (10 g) with diethyl ether (5 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[CH:9]=[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]2=[O:25].C([Sn]([C:41]#[C:42][Si:43]([CH3:46])([CH3:45])[CH3:44])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:26])=[C:3]([F:27])[C:2]=2[C:41]#[C:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:7](=[O:25])[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Yield: 69 %

Procedure:
6.7 g of ethyl 8-bromo-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example Z20), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The product crystallises from the reaction mixture at -18° C. 4.8 g of ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (69% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:9]
Reactant: Nc1nccs1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nccs1)c1cc(Br)ccc1O
Yield: 12 %

Procedure:
Using 5-bromosalicylic acid and 2-aminothiazole as the raw materials, the same operation as the example 16 gave the title compound.
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+].[Cl:19][C:20]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:30])[NH:24]2>>[Cl:19][C:20]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:30])[N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2c(ccc(F)c2Cl)N1
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2Cl)N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 44.8 %

Procedure:
The product is prepared according to the procedure described in example 1c, step 3c, using 248 mg of sodium (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 160 mg of 4-chloro-5-fluoro-2-methyl-2,3-dihydro-1H-indole (reference example 10c). After silica column purification: eluent 99/01 then 98/02 dichloromethane/methanol, 157 mg of 2-[2-(4-chloro-5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid which will be separated into its two enantiomers on a chiral column.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O.C(O)C.N>O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Nc1n[nH]c2ccc([N+](=O)[O-])cc12)c1ccccc1
Agent: N
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]nc(NC(=O)c3ccccc3)c2c1
Yield: 74.6 %

Procedure:
N-(5-Amino-1H-indazol-3-yl)benzamide can be obtained as described in Example 4 from 0.6 g of N-(5-nitro-1H-indazol-3-yl)benzamide, 21 ml of ethanol, 4.2 g of ferrous sulfate, 6.6 ml of water and 5.1 ml of 32% aqueous ammonia. 0.4 g of N-(5-amino-1H-indazol-3-yl)benzamide is thus obtained in the form of a yellow powder melting at 116° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[CH3:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[CH2:18][NH:19][C:20]([C@@H:22]1[C:26]([CH3:28])([CH3:27])[S:25][CH2:24][N:23]1[C:29](=[O:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:21]>C(OCC)(=O)C>[CH3:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[CH2:18][NH:19][C:20]([C@@H:22]1[C:26]([CH3:28])([CH3:27])[S:25][CH2:24][N:23]1[C:29](=[O:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@@H:41]([NH:42][C:5](=[O:7])[CH3:6])[CH:43]([CH3:45])[CH3:44])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:21]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Acetic anhydride (31 μl) and triethylamine (46 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in ethyl acetate (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was reprecipitated from ethyl acetate/n-hexane to obtain the title compound (143 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(CBr)o1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a stirred solution of ethyl 5-methyloxazole-2-carboxylate (5.1 g, 32.87 mmol) and NBS (8.19 g, 46.02 mmol) in carbon tetrachloride (50.0 mL), is added benzoyl peroxide (0.79 g, 3.29 mmol) and the reaction mixture is refluxed for 16 hours. The mixture is cooled to room temperature and filtered through diatomaceous earth. The filtrate is concentrated in vacuum and the crude is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.2:0.8) to give (4.8 g, 62.33%) of the title compound as a light brown oil. ESI/MS m/z (79Br/81Br) 234.1/236.1 [M+H]+.