Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(O)c1
Reaction time: 16 h
Yield: 73.4 %

Procedure:
tert-Butyl N-[2-(2-benzyloxy-4-isopropylphenyl)-ethyl]carbamate (12.00 g) was dissolved in 150 mL of ethanol. To the stirred solution was added 1.10 g of 10% palladium on carbon under ice-cooling, and the mixture was stirred under a hydrogen atmosphere and ordinary pressure at 30° C. for 16 hours. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure to give 6.66 g of tert-butyl N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]carbamate.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:7])C>>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=2)[NH:13][C:12]=1[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNC(=O)OC(C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 5.5 h

Procedure:
To a suspension of 3-(2-tert-butoxycarbonylamino-ethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester (830 mg in 50 mL methanol) was added 8 mL of a 1.25N sodium hydroxide solution and the mixture heated to 75° C. on an oil bath. After 5.5 hours, an additional 3 mL of 1.25N sodium hydroxide were added and the reaction allowed to proceed for 2 more hours. At this time the mixture was cooled to room temperature and the reaction quenched by the addition of pH2 buffer. The mixture was extracted with the ethyl acetate, washed with saturated ammonium chloride solution and the organic portion dried over sodium sulfate. Concentration in vacuo provided the crude acid in quantitative yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][C:28]([C:30]6[O:31][C:32]([CH:35]=O)=[CH:33][CH:34]=6)=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:37][CH3:38])=[N:10]2)=[N:3]1.C1COCC1.[CH3:44][NH:45][CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][C:28]([C:30]6[O:31][C:32]([CH2:35][N:45]([CH3:46])[CH3:44])=[CH:33][CH:34]=6)=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:37][CH3:38])=[N:10]2)=[N:3]1
Reactant: CNC
Reactant: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5ccc(C=O)o5)ccn34)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5ccc(CN(C)C)o5)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)-7-(5-formylfuran-2-yl)imidazo[1,2-a]pyridine-3-carboxamide (36 mg) in 1 mL of a 1:1 DCM:THF mixture was treated at ambient temperature with excess 2.0 M dimethylamine solution in MeOH. The reaction mixture was stirred at ambient temperature for 30 minutes. A large excess of sodium triacetoxyborohydride (10 equivalents) was added, and the reaction stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, dissolved in a small amount of MeOH, and subjected to preparative thin-layer chromatography with a 2% 7N ammonia-MeOH, 8% MeOH in DCM solution as eluent to give the desired product (12.8 mg). MS (ES+APCI) m/z=537 (M+H) detected.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](N)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].[N:29]1C=CC=CC=1.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:29][S:25]([CH3:24])(=[O:27])=[O:26])[CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(N)ccc32)cc1
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(NS(C)(=O)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of 4-(5-amino-3-cyanoindol-1-yl)benzoic acid ethyl ester (0.070 g) in dichloromethane (2 mL) were added methanesulfonyl chloride (0.035 g) and pyridine (0.036 g) at room temperature, and this mixture was stirred at room temperature overnight. This reaction mixture was poured into 1 mol/L hydrochloric acid, this resulting mixture was extracted with ethyl acetate. This organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90-75/25) to give the title compound (0.046 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7](N(CC)CC)C.[C:14](Cl)(=[O:18])[CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[CH3:7][O:5][C:4](=[O:6])[CH2:3][NH:2][C:14](=[O:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCN(CC)CC
Reactant: NCC(=O)O
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCCC(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of glycine hydrochloride (1.00 g, 7.964 mmol) in methylene chloride (40 mL), cooled to 0° under a nitrogen atmosphere, was treated with triethylamine (4.44 mL, 31.86 mmol) and butyryl chloride (0.93 mL, 8.76 mmol), and the mixture stirred at room temperature for 2.5 hours. The reaction was washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum giving the title compound. Purification by silica gel flash chromatography with 25% ethyl acetate/methylene chloride afforded the title compound as a colorless oil (0.776 g, 4.88 mmol, 61%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1.N1C=CC=CC=1C1C=C[C:24]([CH:25]=[O:26])=CC=1>>[N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:24]/[CH:25]=[O:26])=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: O=C/C=C/c1ccc(-c2cncnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 4-(5-pyrimidinyl)-benzaldehyde (prepared as described in Reference Example 25) for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 211 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)[N:13]=2)=[CH:8][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:35](=[O:36])[CH2:34][C:32]#[N:33])[N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:11][CH:10]=3)[C:20]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2C[C@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
Into a 100 mL, round-bottom flask, was placed 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (185 mg, 0.44 mmol, 1.00 equiv), 2-cyanoacetic acid (30.7 mg, 0.36 mmol, 0.80 equiv), HATU (138 mg, 0.36 mmol, 0.80 equiv), triethylamine (91 mg, 0.90 mmol, 2.00 equiv), and N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C. and then extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 101 mg (47%) of 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[H][H]>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: [H][H]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(N)ccc1Cl
Yield: 43.1 %

Procedure:
A solution of 10.0 g (54.8 mmol) 2-chloro-5-nitrobenzonitrile in 500 ml ethanol was hydrogenated at 30 psi by using 0.5 g 5% Pd-C as a catalyst When the hydrogen uptake had ceased, the reaction mixture was filtered and evaporated in vacuo. The residue was recrystallized (ethanol-water) to give 3.6 g (44%) of 5-amino-2-chlorobenzonitrile. M.p. 129°-130° C.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:4][CH2:3]2.[OH-].[Na+]>O1CCOCC1>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 80 °C
Yield: 46.8 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.023 mmol) and sodium hydroxide (0.113 mL, 0.113 mmol) in dioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixture was filtered and the clear solution was purified by HPLC to provide the title compound as a white solid (7 mg, 45%). LCMS: m/e 651.52 (M+H)+, 2.28 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H), 4.81 (s, 1H), 4.71 (s, 1H), 3.53 (br. s., 2H), 3.36-3.26 (m, 2H), 3.07 (s, 3H), 2.96-2.75 (m, 1H), 2.30-2.11 (m, 3H), 1.84-1.06 (m, 19H), 1.74 (s, 3H), 1.22 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:46](=[O:47])[NH:45][C:42]4[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=4)[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(=O)Nc4ccc(F)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), 4-fluorophenyl isocyanate (0.023 mL, 0.205 mmol) was added. The mixture was stirred at room temperature for 4 h. It was then purified by HPLC to give the titled compound (32 mg). MS 521.5 (M+H); UV 204.1, 243.1 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[C:23]([CH3:24])[CH:22]=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1cccc2c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)[nH]c12
Yield: 97.9 %

Procedure:
2.00 g (9.19 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.26 g (8.33 mmol) of 2-amino-3-methylbenzoic acid were treated in the same way as in Example 1 to obtain 2.86 g of the above-identified compound (yield 98.0%). Properties: colorless crystal, Melting point: 221°-225° C., PMR (δppm, DMSO-d6): 2.32 (3H,s), 7.12 (1H,t), 7.51 (1H,d), 7.72 (1H,d), 7.76 (2H,d), 8.19 (2H,d), 11.10 (1H,br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[H-].[Na+].[CH3:11][NH:12][C:13](=[O:15])[CH3:14]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:12]([CH3:11])[C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CNC(C)=O
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ncc(Br)cn1
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-2-chloroprimidine (2.00 g, 10.34 mmol) in THF was added 60% NaH (0.34 g, 14.00 mmol) in mineral oil. After 20 minutes, N-methylacetamide (0.80 g, 11.00 mmol) was added dropwise. After 2 hours, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford N-(5-bromo-pyrimidin-2-yl)-N-methyl-acetamide.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[C:14]([CH3:20])[CH:13]=1.CN(/[CH:24]=[C:25](/[C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33])\[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>C(O)C>[C:32]([C:31]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:20])[N:19]=[CH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(C)(C)C
Reactant: Cc1cc(Cl)ccc1NN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C)c1C(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
N-Ethyldiisopropylamine (1.553 mL, 8.97 mmol) was added to (4-chloro-2-methylphenyl)hydrazine hydrochloride (1.733 g, 8.97 mmol) and (Z)-ethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate (Intermediate #83) (2.04 g, 8.97 mmol) in ethanol (30 mL). The resulting solution was stirred at 90° C. for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with water (2×10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate (0.891 g, 30.9%) as a orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:28]1([CH2:37][C:38](O)=[O:39])[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[C:38](=[O:39])[CH2:37][N:28]1[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2)s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([C:19]#[N:20])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.[CH3:25][C:26]1[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>CC(O)C>[CH3:32][C:30]1[N:31]=[C:26]([CH:25]=[N:1][N:2]2[CH2:3][CH2:4][N:5]([CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH:12]=[C:11]([C:19]#[N:20])[C:10]4[CH:21]=[CH:22][CH:23]=[CH:24][C:9]3=4)[CH2:6][CH2:7]2)[CH:27]=[CH:28][CH:29]=1
Reactant: N#CC1=Cc2ccccc2C(N2CCN(N)CC2)c2ccccc21
Reactant: Cc1cccc(C=O)n1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cccc(C=NN2CCN(C3c4ccccc4C=C(C#N)c4ccccc43)CC2)n1
Reaction time: 4 h

Procedure:
A mixture of 30 parts of 5-(4-amino-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile, 21 parts of 6-methyl-2-pyridinecarboxaldehyde, 1 part of glacial acetic acid, and 250 parts of 2-propanol is heated at the boiling point under reflux with stirring for 4 hours, then stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of tetrahydrofuran and hexane to give 5-{4-[(6-methyl-2-pyridylmethylene)amino]-1-piperazinyl}-5H-dibenzo[a,d]cycloheptene-10-carbonitrile as light brown crystals melting at 200°-202°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)[NH:16][N:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:28][C:29]1([CH3:35])[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([N:33]4[CH2:32][CH2:31][NH:30][C:29]([CH3:35])([CH3:28])[CH2:34]4)=[CH:22][CH:21]=3)[NH:16][N:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Reactant: CC1(C)CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCNC(C)(C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 120 °C
Reaction time: 384 h
Yield: 4.8 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide (0.1 g, 0.27 mmol) and 2,2-dimethylpiperazine (0.124 g, 1.04 mmol) were stirred at 60° C. for 20 mins. Potassium carbonate (0.033 ml, 0.54 mmol) and DMSO (1 ml) were added and the reaction stirred at 120° C. in a sealed tube for 16 days. The reaction mixture was cooled and evaporated. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (6.00 mg, 2.000%) as a colourless gum.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+].Cl>O.O1CCCC1>[F:20][CH:18]([F:19])[O:17][C:10]1[C:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[C:8]([CH3:33])[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:11]=1
Reactant: CCS(=O)(=O)c1ccc(Cc2c(OC(F)F)nc3c(F)ccc(OCC(=O)OC)c3c2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cc2c(OC(F)F)nc3c(F)ccc(OCC(=O)O)c3c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [2-difluoromethoxy-3-(4-ethanesulfonylbenzyl)-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.10 g), methanol (2.0 mL), tetrahydrofuran (2.0 mL), water (2.5 mL) and lithium hydroxide (0.017 mg) was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid and purified by preparative reverse-phase HPLC, using a gradient over 30 minutes of acetonitrile in water to afford title compound as a white solid, 0.070 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:14]([CH3:21])[CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Cc1cc(F)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1-c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A solution of 4-chloro-3-nitropyridine (2.4 g, 15.1 mmol, CAS RN 13091-23-1), 4-fluoro-2-methylphenylboronic acid (2.8 g, 18.2 mmol, CAS RN 139911-29-8), potassium carbonate (6.28 g, 45.4 mmol) and palladium tetrakis-triphenylphosphine (794 mg, 0.76 mmol, CAS RN 14221-01-3) in dioxane (75 mL) was heated to reflux for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and all volatiles were removed under reduced pressure. Column chromatography on silica gel (20-33% EtOAc in n-hexane) afforded 4-(4-fluoro-2-methylphenyl)-3-nitropyridine as a yellow crystalline solid (3.2 g, 90%) which was used in the next step without further purification.
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1cc2ncc(=O)[nH]c2s1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2ncc(Cl)nc2s1
Yield: 39.4 %

Procedure:
A mixture of 91 (6.66 mmol, 1.4 g) in phosphorus oxychloride (21.46 mmol, 2 mL) was heated to reflux for 5 days. Reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (3×). The crude product was purified by chromatography (heptane/ethyl acetate 9/1) to give methyl 3-chlorothieno[2,3-b]pyrazine-6-carboxylate 92 (0.6 g, 40%). NMR (400 MHz, CDCl3) 4.01 (s, 3H), 8.18 (s, 1H), 8.71 (s, 1H). (m/z)=229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:12][C:4]1[C:5]([CH3:11])=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
A mixture of 4-chloro-3,5-dinitro-o-xylene (4.62 g; 0.02 mol), N-bromosuccinimide (3.90 g; 0.022 mol) and carbon tetrachloride (100 ml) is stirred and heated at reflux for 4 hours. The reaction mixture is then irradiated with a light source (60 watt) and refluxing continued for 2 hours. Next, 100 mg of initiator [2,2-azobis(2-methylpropionitrile)] is added and the mixture refluxed for one more hour. The reaction mixture is then cooled to room temperature and stirred under a light source for 48 hours, and filtered. The filtrate is evaporated to dryness in vacuo, and the solid residue recrystallized twice from ethanol to afford 1.35 g of title product.