Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].B>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)Cc2ccc([N+](=O)[O-])cc2)cc1OC
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCCc2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a stirred solution of N-[2-[2-(3,4-dimethoxy-phenyl)-1H-indol-3-yl]ethyl]-2-(4-nitrophenyl)acetamide (90 mg in 3 mL dry tetrahydrofuran) was added 0.79 mL of a 1M solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (0.60 mL) and heated to reflux on an oil bath. After 3 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 96:4) gave the title compound (79 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[BH4-].[Na+]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1cccc(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2′,3′-Difluoroacetophenone (0.337 g, 2.16 mmol) in methanol (15 mL) was treated with sodium borohydride (0.090 g, 2.37 mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and water, and the organic layer was separated, dried over MgSO4, filtered, and concentrated to give 1-(2,3-difluoro-phenyl)-ethanol.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S(O[CH2:13][C:14]2([CH3:17])[CH2:16][O:15]2)(=O)=O)=CC=1.[Cl:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([CH2:13][C:14]3([CH3:17])[CH2:16][O:15]3)[C:26]2=[O:30])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Reactant: O=C1NCCN1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CN2CCN(Cc3ccc(Cl)cc3)C2=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Sodium hydride (99 mg, 2.49 mmol) was added to a solution of 2-methyl-2-oxiranylmethyl toluene-4-sulfonate (500 mg, 2.37 mmol) in DMF (5 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 1 hour. To which a solution of 1-(4-chlorobenzyl)imidazolidin-2-one (633 mg, 2.61 mmol) in DMF (5 ml) was added while cooling in an ice-bath, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether twice. The extracts were combined, washed with water twice and then with brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=3/1) to afford 1-(4-chlorobenzyl)-3-(2-methyl-2-oxiranylmethyl)imidazolidin-2-one (399 mg, 60%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]([CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])C(=O)C(F)(F)F)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5].O.O[Li].O>C1COCC1.CO.CCOC(C)=O>[F:1][C:2]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5]
Reactant: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5cc(F)ccc5F)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CS(=O)(=O)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5cc(F)ccc5F)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 45.9 %

Procedure:
To a solution of 2,5-difluoro-N-[3-(3-{2-[(3-{[[2-(methylsulfonyl)ethyl]-(trifluoroacetyl)amino]methyl}phenyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]benzamide (104 mg, 0.14 mmol) in THF (3 mL), MeOH (0.5 mL), and water (0.5 mL) was added LiOH.H2O (12 mg, 0.28 mmol). The solution was stirred at 50° C. for 4 h, then diluted with 25 mL EtOAc and washed with 1 M aqueous Na2CO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography to generate 42 mg of the title compound as a yellow solid (67 mg, 73% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.65 (s, 1H), 9.55 (s, 1H), 8.85 (d, J=6.7 Hz, 1H), 8.54 (d, J=8.8 Hz, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.42-7.55 (m, 5H), 7.36 (d, J=7.8 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.14 (t, J=6.8 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.51 (d, J=5.3 Hz, 1H), 3.67 (s, 2H), 3.23 (t, J=6.6 Hz, 2H), 3.01 (s, 3H), 2.91 (t, J=6.6 Hz, 2H). MS (ESI) m/z=654 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 92.7 %

Procedure:
To ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.9 g) are added 90% acetic acid (20 ml) and conc. hydrochloric acid (5 ml) and the mixture is refluxed for 2 hours. After cooling, the precipitated crystals are isolated, washed with water, ethanol, and diethyl ether in this order to give 1-cyclopropyl-6,7-difluoro-5-methyl-1,4,-dihydro-4-oxoquinoline-3-carboxylic acid (1.6 g), as colorless needles, m.p. 294°-298° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]2)=[CH:17][N:16]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCN(C)CC4)cnc(N)c23)ccc1N
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCN(C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-(4-methylpiperazin-1-yl)propanamide, and the procedure described in General Procedure F. m/z (M+H)+598.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C1C=CC=CC=1>[Cl:15][CH2:16][CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:19]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: O=C1CCC(c2ccc(NC(=O)CCCl)cc2)=NN1
Yield: 97.2 %

Procedure:
18.9 g (0.10 mole) of 6-(p-aminophenyl)-4,5-dihydropyridaz-3-one and 15.2 g (0.12 mole) of 3-chloropropionyl chloride in 90 ml of absolute benzene are refluxed for 2 hours. The product is filtered off at 10° C., washed first with benzene and then with water, and dried under reduced pressure at 100° C. 27.2 g (97% of theory) of 6-[p-(3-chloropropionylamino)-phenyl]-4,5-dihydropyridaz-3-one are obtained as a colorless substance which, after recrystallization from dimethylformamide/water, melts, with decomposition, at 226°-227° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][S:21]([NH:24][CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)[NH2:13]>C(O)C.O>[CH3:25][NH:24][S:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:12][N:13]=[CH:9][CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:16]=1)(=[O:23])=[O:22]
Reactant: CNS(=O)(=O)Cc1ccc(NN)cc1
Reactant: O=CCSc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNS(=O)(=O)Cc1ccc(NN=CCSc2ccccc2)cc1
Reaction time: 14 h
Yield: 78.9 %

Procedure:
A solution of (phenylthio)acetaldehyde (6.05 g) in absolute ethanol (180 ml) was added over 10 min to a solution of 4-hydrazino-N-methylbenzenemethanesulphonamide hydrochloride (10 g) in water (180 ml) with cooling. After addition of the aldehyde was complete, the mixture was stirred at 5° for a period of 14 h. The precipitated solid was filtered off, washed with water (200 ml), hexane (200 ml) and dried in vacuo to give the title compound (10.95 g), m.p. 110°-112°. T.l.c. (B) Rf 0.5 (KMnO4)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14](F)[CH:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22].C(O)C>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([N:21]([CH3:22])[CH3:20])[CH:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N1CCN(c2nc(F)cc(N(C)C)n2)CC1
Solvent: CCO
Product: CC(=O)N1CCN(c2nc(N(C)C)cc(N(C)C)n2)CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine (1.0 g) was dissolved in 12% dimethylamine-ethanol solution (30 ml) in an autoclave, and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was concentrated under reduced pressure and chloroform was added to the reside. The chloroform solution was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (1.3 g) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:34]([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41])([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(Cl)CCl>[C:34]([O:38][C:39](=[O:46])[C@@H:40]([NH:41][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH2:42][CH:43]([CH3:44])[CH3:45])([CH3:36])([CH3:35])[CH3:37]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)c1ccc(F)c([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 9.26 g of 4-fluoro-3-nitro-benzoic acid in 100 ml of dry DMF 7.43 g of HOBT, 10.54 g of EDC and 8.9 ml of DIPEA were added at 0° C. After 30 min 12.31 g of L-leucin-tert.-butylester-hydrochloride and 8.9 ml of DIPEA were added and the reaction was stirred at it for 4 h. The reaction was then concentrated to about a fifth of its volume and poured into water. It was then extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium carbonate solution and brine, dried over magnesium sulphate and concentrated to yield 17.65 g (100%) of (S)-2-(4-Fluoro-3-nitro-benzoylamino)-4-methyl-pentanoic acid tert-butyl ester as a brown oil, which was used without further purification in the subsequent step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=C([CH:8]=[CH:9][CH:10]=1)N)([O-:3])=[O:2].[H-].[Na+].IC.[CH3:15][N:16]([CH3:19])[CH:17]=O>>[CH3:15][N:16]([CH3:19])[C:17]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)C=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
3-nitroaniline (1.0 g, 7.25 mmol) was dissolved in N,N-dimethylformamide (50 ml), added with sodium hydride (1.7 g, 21.7 mmol) and iodomethane (2.7 ml, 21.7 mmol) at 0° C. The resulting mixture was stirred for 4 hours at room temperature and poured into ice water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (2.0 g, yield: 86%, yellow solid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: CNOC
Reactant: Cc1ccc(Br)cc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H). (2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml), and thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H). (3) A solution of the above N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to −78° C. under argon atmosphere. To the mixture was added dropwise diisobutyl aluminum hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred at the same temperature for one hour. 10% aqueous hydrochloric acid solution (50 ml) was added thereto, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was solidified to give 5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z 213/215 (M+H+MeOH—H2O).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:16][O:15][C@@H:14]([CH:17]([CH3:19])[CH3:18])[O:13][CH2:12]1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:17]([C@H:14]1[O:15][CH2:16][C@H:11]([NH2:10])[CH2:12][O:13]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@H]1OC[C@H](NC(=O)OCc2ccccc2)CO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1OC[C@H](N)CO1

Procedure:
Hydrogenation of 4.07 g (14.6 mMol) of trans-benzyl-(2-isopropyl-[1,3]dioxan-5-yl)-carbamate in 80 ml of EtOAc in the presence of 0.4 g of 10% Pd/C, followed by filtration through Celite and evaporation, yields the title compound: 1H NMR (CDCl3) δ 4.11 (m, 3H), 3.20 (t, 10.5 Hz, 2H), 3.04 (m, 1H), 1.80 (m, 1H), 1.56 (sb, H2N), 0.93 (d, 6H).
Reaction SMILES: ClC1N=CC2C=NNC=2C=1.O1C=CCCC1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]2[CH:24]=[N:25][N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[C:20]=2[CH:19]=1>O1CCOCC1.S(O)(C1C=CC(C)=CC=1)(=O)=O>[Cl:17][C:18]1[N:23]=[CH:22][C:21]2=[CH:20][N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:25]=[C:24]2[CH:19]=1
Reactant: Clc1cc2c(cn1)cnn2C1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Clc1cc2[nH]ncc2cn1
Solvent: C1COCCO1
Product: Clc1cc2nn(C3CCCCO3)cc2cn1
Temperature: 110 °C
Yield: 76 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (11.5 g, 0.075 mol) and 3,4-dihydro-2H-pyran (19 g, 0.225 mol) and Tos-OH (0.13 g 0.75 mmol) in 1,4-dioxane (175 mL) was heated at 110° C. overnight. The mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:0˜20:1) to afford a mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 6-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-c]pyridine (13.5 g, yield 76%) MS (ESI) m/z: m/z: 238 [M+H]+
Reaction SMILES: Cl[CH:2]([CH:6]1OCCO1)[C:3](=[O:5])[CH3:4].Cl.[C:12]([NH2:15])(=[NH:14])[CH3:13].C([O-])(=O)C.[Na+]>C(O)(C)(C)C>[C:3]([C:2]1[N:14]=[C:12]([CH3:13])[NH:15][CH:6]=1)(=[O:5])[CH3:4]
Reactant: CC(=N)N
Reactant: CC(=O)C(Cl)C1OCCO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)c1c[nH]c(C)n1

Procedure:
A mixture of 1.64 g (10 mmole) 2-(1-chloro-2-oxopropyl)dioxolane, 1.89 g (20 mmole) acetamidine hydrochloride, 2.46 g (30 mmole) sodium acetate and 20 ml t-butanol is heated at reflux for 24 hours and the product isolated as in Part A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>[Pd].C1COCC1.CCO.CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)Nc2ccccc2C(=O)O)cc1OC
Reaction time: 16 h
Yield: 78.9 %

Procedure:
Palladium on carbon (5%, 50 mg) was added to a solution of (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (0.50 g, 1.5 mmol) in THF (9.0 mL), EtOH (1.0 mL) and AcOH (1 drop). The suspension was stirred under an atmosphere of hydrogen for 16 h and filtered. The filtrate was concentrated under reduced pressure and the crude product was recrystallised from EtOAc/petrol to give 2-[[3-(3,4-dimethoxyphenyl)-1-oxopropyl]amino]benzoic acid (0.39 g, 77%) as a colourless crystalline solid; mp 137° C., lit. [24] 136-137.5° C.; δH (500 MHz, DMSO-d6) 2.68 (t, J=7.5 Hz, 2H, CH2CO), 2.87 (t, J=7.5 Hz, 2H, CH2Ar), 3.68 (s, 3H, OCH3), 3.70 (5, 3H, OCH3), 6.74 (d, J5′,6′=8.2 Hz, 1H, H6′), 6.82 (d, J5′,6′=8.2 Hz, 1H, H5′), 6.86 (s, 1H, H2′), 7.12 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.57 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.95 (d, J3,4=8.0 Hz, 1H, H3), 8.47 (d, J5,6=8.0 Hz, 1H, H6), 11.11 (s, 1H, NH), 13.57 (br s, 1H, CO2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13]1[N:18]=[C:17](O)[CH:16]=[C:15]([CH3:20])[N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:17]1[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([CH:12]=[CH:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(/C=C/c2nc(C)cc(O)n2)c(OC)c1
Product: COc1ccc(C=Cc2nc(C)cc(Cl)n2)c(OC)c1
Yield: 59.2 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(2,4-dimethoxy-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.33 g, 1.22 mmol) in POCl3 (2.24 ml, 24.5 mmol) at 130° C. for 4.5 h there was obtained 4-chloro-2-[2-(2,4-dimethoxy-phenyl)-vinyl]-6-methyl-pyrimidine (0.21 g, 60%) as a light yellow solid. EI mass spectrum, m/e: 290 (M calculated for C15H15ClN2O2: 290).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:41][C:32]1[C:33]([C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:15]([CH2:16][CH:17]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH:3]=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=CCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
A solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid methyl ester (350 mg, 1.68 mmole) in anhydrous toluene (20 ml) was cooled down to −40° C. in a dry ice/acetonitrile bath. DIBAL-H (1.25 ml, 1.5M solution in toluene, Aldrich) was added in a dropwise fashion. The resulting mixture was stirred at −40° C. for 3 hours and then quenched with 0.01N HCl (aq.). The crude material was concentrated in vacuo and then extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo. Preparative HPLC (YMC, 75×30 mm, 25 ml/min, 70-100% CH3CN) afforded the title compound as an oil, 0.15 g (45%). MS(ES) m/e 566.2 (M+).
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH3:31])=[N:29][CH:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[C:30]([CH3:31])=[N:29][CH:28]=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1ncnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Yield: 24.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (80 mg, 0.119 mmol), DCM (4.0 mL) and TFA (1.0 mL, 13.0 mmol) for 3 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (15 mg, 24%) as a white powder. LCMS: m/z=514.8 (M−1); 1H NMR (400 MHz, D2O) δ 7.86 (s, 1H), 6.89 (s, 1H), 5.36-5.28 (m, 1H), 4.78-4.66 (m, 1H assumed; obscured by solvent residual peak), 4.54-4.44 (m, 1H), 4.42-4.30 (m, 1H), 2.35 (s, 3H), 1.25 (s, 6H).