Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.[C:20](Cl)(Cl)=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][C:12]1[N:13]=[C:9]([N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:20]2=[O:21])[S:10][C:11]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1sc(Nc2ccccc2N)nc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(-n2c(=O)[nH]c3ccccc32)nc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a suspension of ethyl 2-(2-aminophenylamino)-4-methylthiazole-5-carboxylate (0.24 g, 0.87 mmol) in dichloromethane (12 mL) was added phosgene solution (purum, ˜20% in toluene, 0.48 mL, 0.91 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 16 h followed by the addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL), washed with water and brine, dried over sodium sulfate, filtered, concentrated to small volume, and triturated with diethyl ether (5 mL) to precipitate the product. The solid was collected by filtration, washed with water (3×5 mL) and hexanes (5 mL), and dried in vacuo to afford ethyl 4-methyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)thiazole-5-carboxylate as a white solid (0.21 g, 80% yield): MS (ES+) m/z 304.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]1=[S:21].[N:22]1([C:31]([N:33]2[CH2:36][C:35]([F:38])([F:37])[CH2:34]2)=N)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C.O1CCOCC1>[F:37][C:35]1([F:38])[CH2:36][N:33]([C:31](=[NH:22])[NH:1][CH2:2][CH2:3][CH2:4][N:5]2[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]2=[S:21])[CH2:34]1
Reactant: COc1ccc(F)cc1-c1cc(=O)[nH]c(=S)n1CCCN
Reactant: N=C(N1CC(F)(F)C1)n1nnc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1cc(=O)[nH]c(=S)n1CCCNC(=N)N1CC(F)(F)C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a mixture of 1-(3-aminopropyl)-6-(5-fluoro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (prepared in an analogous manner to Example 6; 50 mg, 0.14 mmol) and 1-(1H-benzotriazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)methanimine (47.5 mg, 0.174 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) under nitrogen and heated at 60° C. under nitrogen for 1 h. The reaction mixture was cooled to room temperature, and treated with 4N HCl in dioxane (0.25 mL). The mixture was stirred at room temperature for 10 min, then concentrated in vacuo and azeotroped with heptanes (3×10 mL). The residue was dissolved in water (1 mL) and purified using medium pressure reverse-phase (C18) chromatography (100:0 to 70:30 water/acetonitrile) to give the title compound as a white solid (22 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:20]1[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 79 %

Procedure:
To a mixture of 4-(trifluoromethyl)phenylboronic acid (285 mg, 1.5 mmol), 2-bromo-3-methyl-5-nitropyridine (216 mg, 1.0 mmol), and potassium carbonate (345 mg, 2.5 mmol) in water (1.5 mL) and dioxane (6 mL) was added tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol). The resulting mixture was stirred at 80° C. for 4.5 hours. The mixture was cooled to room temperature. Ethyl acetate was added and the mixture was washed with water, then brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 3-methyl-5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (223 mg, 79%). 1H NMR (400 MHz, CDCl3, δ): 9.35 (s, 1H), 8.42 (s, 1H), 7.77 (d, 2H), 7.69 (d, 2H), 2.51 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][CH:7]2[CH2:11][CH2:10][N:9](C(OCC)=O)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:19]>>[ClH:1].[ClH:19].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2)C1
Agent: Cl
Product: Clc1ccc(NC2CCNC2)cc1
Yield: 96 %

Procedure:
A mixture of ethyl 3-(4-chloroanilino)pyrrolidine-1-carboxylate (7.20 g) and conc. hydrochloric acid (72 ml) is heated under reflux over a period of 20 hours. The reaction mixture is concentrated in vacuo, and the residue is crystallized from methanol-isopropanol to give 3-(4-chloroanilino)pyrrolidine dihydrochloride (6.99 g) as crystals melting at 120° to 143° C. The yield is 96%.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH2:36][CH3:37])[CH:17]([C:19]4[N:20]=[CH:21][C:22]5[N:27](COCC[Si](C)(C)C)[CH:26]=[CH:25][C:23]=5[N:24]=4)[CH3:18])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>CN(C=O)C>[N:24]1[C:23]2[CH:25]=[CH:26][NH:27][C:22]=2[CH:21]=[N:20][C:19]=1[CH:17]([N:16]([CH2:36][CH3:37])[C:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[CH:15]=[CH:14][N:13]=1)[CH3:18]
Reactant: CCN(c1nccc(Nc2cc(C3CC3)[nH]n2)n1)C(C)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(c1nccc(Nc2cc(C3CC3)[nH]n2)n1)C(C)c1ncc2[nH]ccc2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 64.7 %

Procedure:
To a stirred solution of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-ethyl-N2-(1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethyl)pyrimidine-2,4-diamine (103.9 mg, 0.20 mmol) in anhydrous DMF (4.7 mL) was added ethylenediamine (0.10 mL, 1.60 mmol) followed by tetrabutylammonium fluoride (1M in THF, 0.60 mL, 0.60 mmol), and the reaction mixture was stirred at 80° C. under N2 for 20 h. The reaction mixture was poured into EtOAc, and the organic layer was washed with 10% aq. NaOH solution, water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography to afford 50.4 mg (64.7%) of racemic N2-(1-(5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-ethylpyrimidine-2,4-diamine. Chiral SFC chromatography of racemic N2-(1-(5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-ethylpyrimidine-2,4-diamine (50.4 mg, 0.13 mmol) afforded the corresponding two enantiomers:
Reaction SMILES: [OH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:41][CH2:42][OH:43])[C:20]=1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:44](Cl)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:1][C@H:2]([C:13](=[O:14])[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:41][CH2:42][O:43][C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:20]=1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a stirred solution of tert-butyl ((3S)-3-hydroxy-4-{[1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}-4-oxobutyl)carbamate (2.5 g) in N,N-dimethylformamide (25 ml) were added trityl chloride (1.25 g), triethylamine (1.78 ml) and 4-dimethylaminopyridine (52.1 mg), and the mixture was stirred for 1 hour. The reaction mixture was warmed up to 60° C. and stirred at the same temperature for 2 days. Water was added to the mixture, and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave an oil, which was purified by column chromatography on silica gel (methylene chloride:ethyl acetate=5:1) to give tert-butyl [(3S)-3-hydroxy-4-oxo-4-({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)butyl]carbamate (1.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([CH2:31][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:33][CH:34]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(Cn3cnc4c3c(=O)n(C)c(=O)n4C)cc2)cc1
Yield: 45.9 %

Procedure:
A solution of 1,3-dimethylxanthine (99 mg), potassium carbonate (135 mg), 4-(4-methylbenzoyl)benzyl bromide (201 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:5) and recrystallized from ethyl acetate-isopropyl ether to provide the title compound as colorless solid (98 mg).
Reaction SMILES: [H-].[Li+].C[O:4][C:5]1[NH:6][CH2:7][CH2:8][CH:9]=1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[OH-].[Li+]>O.C(OCC)(=O)C.C1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:6]2[CH2:7][CH2:8][CH2:9][C:5]2=[O:4])=[O:17])=[CH:14][CH:13]=1
Reactant: COC1=CCCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 25 °C

Procedure:
276 mg. of lithium hydride (98%), 40 ml. of benzene and 4.2 g. of 2-methoxypyrroline are boiled at reflux for 2 hours under nitrogen and while stirring well. After cooling to 25° C., 6.6 g. of p-methoxybenzoyl chloride dissolved in 25 ml. of benzene are added and the resulting mixture is stirred under reflux for 2 hours and at room temperature for 16 hours. 100 ml. of ethyl acetate followed by 3.0 g. of lithium hydroxide (98%) dissolved in 25 ml. of water are added to the mixture at room temperature within 15 minutes. The organic phase is washed neutral with water, dried over sodium sulfate and evaporated under reduced pressure. After recrystallization from ethanol, there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([O:28]C)[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][CH2:32][OH:33])[C:12]=2[CH:11]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][CH2:32][OH:33])[C:12]=2[CH:11]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4OC)cc1n2CCCO)C(=O)NC3=O
Agent: BrB(Br)Br
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCO
Yield: 64 %

Procedure:
The reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(3-hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OH) (105) prepared as described in example 58 with BBr3 using the procedure described in example 80 and with a reaction time of 90 minutes gave 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OH) (106) in a 64% yield as an orange powder, mp 270–273° C. 1H NMR δ [(CD3)2SO] 11.01 (br s, 1H), 9.35 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.44 (dd, J=8.3, 8.3 Hz, 1H), 7.20–7.11 (m, 3H), 4.61 (br t, 1H), 4.47 (t, J=6.9 Hz, 2H), 3.68 (s, 3H), 3.42 (m, 2H), 1.88 (m, 2H). Found: C, 64.16; H, 4.55; N, 6.01. C24H19ClN2O5 requires C, 63.93; H, 4.25; N, 6.21.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][S:16][CH2:15][CH:14]1[C:19](O)=[O:20])=[O:12])([CH3:9])([CH3:8])[CH3:7].P(C#N)([O-])(OCC)=O.O>O1CCCC1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][S:16][CH2:15][CH:14]1[C:19]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:20])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)O
Reactant: C1CCNC1
Agent: CCOP(=O)([O-])C#N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCSCC1C(=O)N1CCCC1
Yield: 74 %

Procedure:
followed by a solution of pyrrolidine (2.0 ml) in 10 ml of tetrahydrofuran, was added at 0° C. under a stream of nitrogen to a solution of 5.0 g of 4-(t-butoxycarbonyl)thiomorpholine-3-carboxylic acid in 100 ml of tetrahydrofuran. After the mixture had been stirred for I hour, a solution of 3.6 g of ethyl cyanophosphate in 10 ml of tetrahydrofuran was added to the mixture and the mixture was stirred for 5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to yield 461 g (74%) of 4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]([O:39][CH3:42])([CH3:37])[CH3:38])=[CH:32][CH:33]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.33 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.05 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.08 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 15 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH2:13].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:8][C:7]1[CH:6]=[C:5]([C:9]([F:11])([F:12])[F:10])[CH:4]=[C:3]([NH:13][C:17](=[O:18])[CH2:16][O:15][CH3:14])[C:2]=1[Cl:1])=[O:18]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(N)c1Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C(F)(F)F)cc(NC(=O)COC)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzotrifluoride (4.2 g) in pyridine (80 ml) is added dropwise methoxyacetyl chloride (4.0 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (5.0 g) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.ClC(Cl)(Cl)[CH:16]=[O:17]>C(OCCCC)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:16]=[O:17])[CH2:10][CH2:9]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cc1ccccc1N1CCNCC1
Solvent: CCCCOCCCC
Product: Cc1ccccc1N1CCN(C=O)CC1
Temperature: 80 °C

Procedure:
With vigorous stirring, 437 mmol (77 g) of 2-methylphenylpiperazine are added to a solution of 415 mmol (61.3 g) of trichloroacetaldehyde in 400 ml of dibutyl ether. The reaction mixture is heated at 80° C. for 1 hour and, after cooling, concentrated to yield the expected product.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:13][CH3:14])[C:7]([O:15][CH3:16])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:13][CH3:14])[C:7]([O:15][CH3:16])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Solvent: CCO
Product: COc1ccc(N)c(C(=O)O)c1OC

Procedure:
To a solution of 23.4 g (104 mmol) 6-nitro-2,3-dimethoxy-benzoic acid in ethanol 2.5 g Pd/C were added and treated with 1 bar H2 for 24 h. The catalyst was removed by filtration over Celite, the solution evaporated, the residue was dissolved in 300 ml dioxane and lyophilized.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]3[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:30]>>[ClH:30].[ClH:30].[N:1]1([C:6]2[CH:23]=[CH:22][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(N3CCCC3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(cc1N1CCCC1)OCCNC2
Yield: 73.3 %

Procedure:
A solution of tert-butyl 8-(pyrrolidin-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (110 mg, 0.345 mmol) in 4N hydrogen chloride-ethyl acetate (2 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (74.0 mg, 73.3%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:31]([CH3:40])([CH3:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:31]([CH3:40])([CH3:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21](NCC)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.ClC1C=CN(CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)C(=O)N=1.[CH3:53][CH2:54][O-:55].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([O:55][CH2:54][CH3:53])=[N:20][C:19]2=[O:27])=[CH:6][CH:7]=1
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Reactant: CC[O-]
Agent: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and NaOEt in EtOH. M/e+ 381 for C20H18ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.36 (d, J=7.0 Hz, 1H), 8.17 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 6.92 (m, 1H), 6.89 (d, J=6.9 Hz, 1H), 5.71 (d, J=6.9 Hz, 1H), 5.60 (s, 2H), 4.40 (q, J=6.9 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H) ppm.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][N:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Br:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:20]([NH:19][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])=[S:21])[CH:6]=[CH:5][N:4]=1
Reactant: NCc1ccnc(Br)c1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: Cl
Product: S=C(NCc1ccnc(Br)c1)Nc1cccc(Cl)c1Cl
Yield: 84 %

Procedure:
Prepared in 84% yield from the product of Example 144A and 2,3-dichlorophenylisothiocyanate according to the procedure described for Example 141B and 141C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[NH:8]C(OC(C)(C)C)=O)=[O:6])[CH2:2][CH3:3].[CH3:24][S:25]([OH:28])(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[CH2:1]([NH:4][C:5]([N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[NH2:8])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)N(Cc1ccc(C)cc1)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCNC(=O)N(N)Cc1ccc(C)cc1
Reaction time: 21 h
Yield: 69.2 %

Procedure:
To a solution of 2-(propylaminocarbonyl)-2-(4-methylphenylmethyl)hydrazinecarboxylic acid, 1,1-dimethylethyl ester (3.0204 g, 9.397 mmol) in dichloromethane (25 mL) was added methanesulfonic acid (762 μL, 11.7 mmol) and the mixture stirred for 21 h. The mixture was then concentrated in vacuo to an oil and recrystallized (ethyl acetate) to afford the title compound as a white solid (2.0639 g, 6.502 mmol, 69%): mp 108.5-111.4° C.; 1H NMR (DMSO-d6) δ 7.56 (s, 1H), 7.18 (s, 4H), 4.67 (s, 2H), 3.06 (t, 2H, J=7.0 Hz), 2.35 (s, 3H), 2.81 (s, 3 H), 1.44 (m, 2H), 0.82 (t,. 3H, J=7.5 Hz); 13C NMR (DMSO-d6) δ 157.7, 138.0, 132.5, 129.9, 128.8, 52.7, 42.7, 40.6, 23.3, 21.4, 11.9; IR (CHCl3) 3416, 3009, 2967, 2936, 2877, 1691, 1543 cm−1. Anal. Calcd. for C12H19N3O.CH4O3S: C, 49.19; H, 7.30; N, 13.24. Found: C, 48.87; H, 7.32; N, 13.28.