Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.CC(C)=O>CC(C)=O>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCC(=O)OC(C)(C)C)ccc12

Procedure:
The compound ethyl 3-phenyl-3-(6-hydroxyindol-3-yl)propionate 4 prepared analogously to Example 1.1-1.3 (3.23 mmol) is stirred overnight at 60° C. with 0.94 ml (6.4 mmol) of tert-butyl bromoacetate and 1.8 g (13 mmol) of potassium carbonate in 20 ml of acetone. When the reaction is complete (TLC check toluene/acetone 4:1), the residue is filtered off, the solution is evaporated, and the crude product is purified by chromatography on silica gel (eluent toluene/acetone 9:1), giving ethyl 3-phenyl-3-[6-(tert-butoxycarbonylmethoxy)indol-3-yl]propionate.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O1CCOCC1>[CH2:34]([O:33][C:31]([N:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCNC(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CCN(C(=O)OCc1ccccc1)C(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Temperature: 25 °C
Yield: 72.9 %

Procedure:
To the amine 3B (7.80 g, 21.6 mmol) and NaHCO3 (2.82 g, 33.6 mmol, 1.55 eq) in 40 mL anhydrous dioxane was added benzyl chloroformate (4.80 g, 28.1 mmol, 1.3 eq) at 0° C. over 5 mins. The ice bath was removed, and the mixture was allowed to warm to RT overnight. Solvents were removed in vacuo; the residue was diluted with 50 mL of water and 100 mL of EtOAc. The organic phase was separated, and the aqueous phase was further extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over Na2SO4, and concentrated. The residue was chromatographed on SiO2 to afford 7.8 g (73%) of product 3C as a colorless liquid along with the recovery of 1.02 g starting material. ESI-MS:m/z 496.5 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([O:14][CH3:15])=[O:13])[CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl.[C:17]([O-:20])(O)=[O:18].[Na+].Cl[S:23]([C:26]1[C:38]([CH3:39])=[CH:37][C:29]([O:30][CH:31]([CH2:35][CH3:36])C(O)=O)=[CH:28][C:27]=1[CH3:40])(=[O:25])=[O:24]>O1CCOCC1>[C:8]([O:7][C:5]([NH:4][CH2:3][CH:2]([NH:1][S:23]([C:26]1[C:27]([CH3:40])=[CH:28][C:29]([O:30][CH2:31][CH2:35][CH2:36][C:17]([OH:20])=[O:18])=[CH:37][C:38]=1[CH3:39])(=[O:25])=[O:24])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: CCC(Oc1cc(C)c(S(=O)(=O)Cl)c(C)c1)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C(CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)O)cc1C

Procedure:
A slurry of H-Dap(Boc)-OMe.HCl (19) (8.0 g, 31.4 mmol) and NaHCO3 (38.6 g, 460 mmol) in 140 mL dioxane/28 mL H2O was cooled to 5° C. with an ice bath. To this slurry was added a solution of the 4-(chlorosulfonyl)-3,5-dimethylphenoxybutanoic acid, 18 (14.0 g 46 mmol) in dioxane (140 mL) dropwise over a period of 75 minutes. After an additional 2 hr the reaction mixture was filtered and the filtrate concentrated in vacuo. To the residue was added water (total volume of 420 mL) and then this was extracted with 75 mL MTBE. The aqueous phase was made acidic (pH=4) using 3 N HCl (aq.) then extracted with EtOAc (300 mL). The EtOAc extract was dried over Na2SO4, filtered and concentrated in vacuo leaving 10.2 g of desired product, 20 (20.9 mmol, 66.5% based on 19, 45% based on 18).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]1([CH:11]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]3=[N:15][NH:16][CH:17]=[C:18]23)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1cccc2ccccc12
Product: CCCC1=C(C(=O)OCC)C(c2cccc3ccccc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from naphthalene-1-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23](Br)[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ncc2c(c1O)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
A suspension of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (5.0 g, 11.7 mmol) and 10% palladium on carbon (500 mg) in industrial methylated spirits (120 mL), ethyl acetate (25 mL), dimethylformamide (25 mL) and triethylamine (25 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 20 h. The reaction vessel was purged with nitrogen then the reaction mixture was filtered through celite. The filtrate was evaporated in vacuo. The resultant brown residue was suspended in aqueous hydrochloric acid (1M, 40 mL) and sonicated for 20 minutes then filtered to afford the title compound as a beige solid (4.0 g, 98%). 1H NMR (DMSO-D6, 300 MHz): 9.27 (d, J=0.8 Hz, 1H), 8.73-8.65 (m, 2H), 8.19 (d, J=7.9 Hz, 2H), 7.78-7.69 (m, 1H), 7.65-7.54 (m, 3H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=O)[C:4]=2[NH:3][CH:2]=1.S(Cl)([Cl:15])=O>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([Cl:15])=[O:12])[C:4]=2[NH:3][CH:2]=1
Reactant: O=C(O)c1cccc2nc[nH]c12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc2nc[nH]c12

Procedure:
The above reaction conditions are as follows: benzimidazole-4-carboxylic acid is reated with thionyl chloride at temperature of 0˜80° C. in a molar molecular ratio of thionyl chloride to benzimidazole-4-carboxylic acid is 1˜20 times, to produce benzimidazole-4-carbonyl chloride, and then benzimidazole-4-carbonyl chloride is reacted with an amine in an organic solvent at temperature of 0˜100° C. to produce benzimidazole-4-carboxamide derivatives. Wherein the organic solvent comprises dichloroethane, 1,1,2-trichloroethane, chloroform, tetrachloroethylene, benzene, toluene, xylene, chlorobenzene or dichlorobenzene, and so on.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>CCOCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH3:16])=[CH:11][N:12]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: C[Mg+]
Reactant: Cc1cc(Br)ccc1-c1ncc(C=O)s1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(Br)ccc1-c1ncc(C(C)O)s1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A suspension of 2-(4-bromo-2-methyl-phenyl)-thiazole-5-carbaldehyde (1.9 g, 6.7 mmol) in ether at 0° C. is treated with 3.0 M MeMgBr (5 ml, 15 mmol) in diethyl ether (50 ml). The reaction mixture is stirred for 2 hours then carefully diluted with water. Acidified with aq. sat. NH4Cl. The aqueous layer is extracted with DCM (2×100 ml). The combined organic layers are dried over magnesium sulphate, filtered and evaporated to dryness to give 1.80 g of crude product. The crude product is purified by flash chromatography on silica gel to give 1-[2-(4-bromo-2-methyl-phenyl)-thiazol-5-yl]-ethanol (1.40 g).
Reaction SMILES: ClC1C=CC(OC2C=CC(N[C:14](=S)[NH:15][C@@H:16]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:18])=CC=2)=CC=1.[F:37][C:38]1[CH:51]=[CH:50][C:41]([O:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1.C(N1C=CN=C1)(N1C=CN=C1)=[O:53].CCOC(C)=O>C1COCC1.O>[F:37][C:38]1[CH:51]=[CH:50][C:41]([O:42][C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:14](=[O:53])[NH:15][C@@H:16]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:18])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1
Reactant: O=C(NCCN1CCCC1)[C@H](Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCN1CCCC1
Temperature: 65 °C
Yield: 27.2 %

Procedure:
To a solution of (S)-2-amino-3-phenyl-N-(2-pyrrolidin-1-yl-ethyl)-propionamide (Example 9, step C) (0.079 g, 0.3 mmol) in THF (3 mL) was added 4-(4-fluoro-phenoxy)-phenylamine (0.124 g, 0.61 mmol). After addition of 1,1′-carbonyldiimidazole (0.063 g, 0.39 mmol), the reaction mixture was heated to 65° C. for 6 h. EtOAc (10 mL) and H2O (10 mL) were then added. The aqueous layer was extracted with EtOAc (3×20 mL) and CH2Cl2 (2×20 mL). The combined organic layers were washed with brine and dried (Na2SO4), and the solvent was removed. Column chromatography using 2–20% MeOH/CH2Cl2 gave 0.04 g (27%) of the desired product. MS (electrospray): mass calculated for C28H31FN4O3, 490.24; m/z found, 491.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.8 (s, 1H), 7.23–7.15 (m, 5H), 6.92–6.88 (m, 3H), 6.83–6.79 (m, 2H), 6.77–6.75 (m, 2H), 6.64 (d, J=8.2 Hz, 1H), 4.58 (dd, J=14.6, 8.0 Hz, 1H), 3.29–3.13 (m, 2H), 3.09 (dd, J=13.5, 6.5 Hz, 1H), 2.96 (dd, J=13.4, 8.0 Hz, 1H), 2.54–2.48 (m, 3H), 2.42–2.37 (m, 6H), 1.70–1.67 (m, 4H).
Reaction SMILES: N1C2C=CC=CC=2N=C1C1C2C(=CC(C(O)=O)=CC=2)NN=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[CH:40]=[C:39]3[C:35]([C:36]([CH:41]=O)=[N:37][NH:38]3)=[CH:34][CH:33]=2)=[O:31])=[CH:25][CH:24]=1.[F:43][C:44]1[C:49]([F:50])=[CH:48][C:47]([NH2:51])=[C:46]([NH2:52])[CH:45]=1>>[F:43][C:44]1[C:49]([F:50])=[CH:48][C:47]2[NH:51][C:41]([C:36]3[C:35]4[C:39](=[CH:40][C:32]([C:30]([NH:29][C:26]5[CH:25]=[CH:24][C:23]([OH:22])=[CH:28][CH:27]=5)=[O:31])=[CH:33][CH:34]=4)[NH:38][N:37]=3)=[N:52][C:46]=2[CH:45]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=Cc1n[nH]c2cc(C(=O)Nc3ccc(O)cc3)ccc12
Agent: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Product: O=C(Nc1ccc(O)cc1)c1ccc2c(-c3nc4cc(F)c(F)cc4[nH]3)n[nH]c2c1

Procedure:
Using the same procedure as for the synthesis of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid in Example 53(a), step (ii), N-(4-hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide and 4,5-difluoro-1,2-phenylenediamine gave 3-(5,6-difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide as a tan solid. 1H NMR (DMSO-d6) δ 13.99 (1H, s), 13.27 (1H, s), 10.21 (1H, s), 9.25 (1H, s), 8.52 (1H, d, J=8.7 Hz), 8.21 (1H, s), 7.85 (1H, d, J=9.0 Hz), 7.80 (1H, t, J=9.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.47 (1H, t, J=9.8 Hz), 6.75 (2H, d, J=8.7 Hz). MS (APCI positive) 406.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[SH2]=N.[C:14]1([NH:20][C:21](C2C=CC=CC=2C(O)=O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:1]1([NH:7][C:21]([NH:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)NC1CCCCC1
Yield: 88.7 %

Procedure:
A mixture of 1.0 g cyclohexylamine and 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, under stirring. The reaction mixture was stirred for 80 minutes at room temperature, then diluted with 150 ml water. The precipitated solid product was cooled, filtered, washed with water and dried. 1.0 g 1-phenyl-3-cyclohexylurea was obtained with a melting point of from 182° to 184° C.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:5]([CH2:36][CH3:37])[CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:34][CH3:35])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([C:24](=O)[CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:18][CH:17]=3)=O)[CH3:4].O.NN>C(O)CO.O>[ClH:1].[ClH:1].[CH2:31]([N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][CH2:25][CH2:24][C:19]1[CH:18]=[CH:17][C:16]2[N:15]([CH2:34][CH3:35])[C:14]3[C:22]([C:21]=2[CH:20]=1)=[CH:23][C:11]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:3][CH3:4])[CH2:36][CH3:37])=[CH:12][CH:13]=3)[CH3:32]
Reactant: CCN(CC)CCCC(=O)c1ccc2c(c1)c1cc(C(=O)CCCN(CC)CC)ccc1n2CC
Agent: Cl
Agent: NN
Solvent: O
Solvent: OCCO
Product: CCN(CC)CCCCc1ccc2c(c1)c1cc(CCCCN(CC)CC)ccc1n2CC
Temperature: 165 °C

Procedure:
A solution of 11.0 g (0.02 mole) of 3,6-bis(4-diethylaminobutryl)-9-ethylcarbazole dihydrochloride and 25 ml of an 85% aqueous hydrazine hydrate solution is dissolved in 200 ml of ethylene glycol and heated to a temperature of 165°C for a period of 18 hours. The reaction mixture is cooled and diluted with water whereupon the free base of the desired compound separates as an oil. The product is separated by decantation, washed with water, dissolved in diethyl ether and the ethereal solution dried over magnesium sulfate. The dried solution is concentrated to a small volume and placed on an aluminum oxide chromatographic column and eluted with methylene chloride. The eluate is converted to its hydrochloride salt and crystallized from a methanol-ethyl acetate solution. Recrystallization from acetone with two additional recrystallizations from a methylene chloride-acetone solution results in the preparation of 3,6-bis(4-diethylaminobutyl)-9-ethylcarbazole dihydrochloride having a m.p. 172°-4° C; and λmaxEtOH 240; and E1cm1% 907.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[Cl:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18]>ClC(Cl)C>[Cl:11][C:12]1[C:16]([CH:4]=[O:5])=[CH:15][NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18].[Cl:11][C:12]1[CH:16]=[C:15]([CH:4]=[O:5])[NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CN(C)C=O
Reactant: COC(=O)c1[nH]ccc1Cl
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c(C=O)cc1Cl
Product: COC(=O)c1[nH]cc(C=O)c1Cl
Yield: 27 %
Yield: 27 %

Procedure:
DMF (0.579 mL, 1.48 mmol) was cooled to 0° C. under nitrogen. POCl3 (0.647 mL, 6.93 mmol) was added to the cold DMF and stirred at 0 oC, and a solid formed. Dichloroethane (2 mL) was added to the solid followed by the addition of methyl 3-chloro-1H-pyrrole-2-carboxylate (1.00 g, 6.26 mmol) in dichloroethane (2 mL). The reaction mixture was stirred for 10 minutes at 0° C. and heated to reflux until the starting material was no longer evident by TLC. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with saturated NaHCO3, dried over MgSO4, filtered and the EtOAc evaporated. Purification was accomplished by silica gel column chromatography (0-30% EtOAc/hexanes) to afford the title compound (0.319 g, 27%), and methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (0.320 g, 27%). 1H NMR (400 MHz, Acetone-d6) δ ppm 11.83 (br. s., 1H), 9.89 (s, 1H), 7.72 (s, 1H), 3.86 (s, 3H). LCMS: m/z=188.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H].Cl.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23]Cl)[CH3:20]>CN(C=O)C.O>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:20]
Reactant: [H][H]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
NaH (14.4 g of 60%, 360 mmol, 3 eq) was added portion-wise under argon to a suspension of carbazole (1) (20 g, 119.8 mmol, 1 eq) in dry DMF (200 mL). The mixture was stirred at room temperature for 30 min until the evolution of the hydrogen ceased. 2-Diethylaminoethylchloride hydrochloride (31 g, 180 mmol, 1.5 eq) was added in portion-wise at room temperature. The reaction mixture was stirred for 20 min at room temperature, then at 60° C. for 3 hrs (TLC monitoring), and poured into cold water (1 L). The product was extracted with EtOAc (5×200 mL); the organic layer was back extracted with 10% HCl (400 mL) and acidic layer was extracted with EtOAc to remove the un-reacted carbazole. The pH of aqueous layer was adjusted to about 9 with K2CO3 and the product extracted again with EtOAc. Evaporation of the solvent afforded 29.5 g (93%) of 9-(2-diethylaminoethyl)carbazole (68) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:16])([F:15])[C:10]([O:12]CC)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:30][C:31]1[N:32]=[CH:33][C:34]([CH2:37][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:10](=[O:12])[C:9]([F:8])([F:15])[F:16])=[CH:35][CH:36]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Temperature: 62.5 °C
Reaction time: 7.5 h
Yield: 71.8 %

Procedure:
In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g (0.1 mol) of 2-aminopyridine was dissolved. To the solution, 21.3 g (0.15 mol) of ethyl trifluoroacetate was added, followed by stirring at 60 to 65° C. for 7.5 hours. After concentration under reduced pressure (90 hPa, 40° C.), the residue was cooled on ice, and 20 mL of toluene and 10.5 g (0.05 mol) of trifluoroacetic anhydride were added to the residue, followed by stirring at room temperature for 1 hour. Subsequently, 16.2 g (0.1 mol) of 2-chloro-5-chloromethylpyridine, 20 mL of dimethylformamide, and 16.6 g (0.12 mol) of potassium carbonate were added, followed by stirring under a reduced pressure of 110 hPa at 60 to 65° C. for 4 hours. After concentration under reduced pressure (90 hPa, 50° C.), 25 mL of methanol was added to the reaction liquid, and the mixture was added to 250 mL of hot water of 50° C. Then, the mixture was cooled to room temperature with stirring. Crystals were filtered, and washed with 90 mL of water and 90 mL of toluene. The obtained crystals were dried under reduced pressure at 60° C. Thus, 22.68 g of the target compound was obtained (Percentage Yield: 72.0%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2([O:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22][CH2:21]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2([O:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH2:22][CH2:23]2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCC1
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2c(N)nc3c(c2n1CC1(OCCS(C)(=O)=O)CCC1)CCCC3
Yield: 69.1 %

Procedure:
A mixture of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 26, 0.500 g, 1.16 mmol) and platinum(IV) oxide (0.5 g) in trifluoroacetic acid (5 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 1 day. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (20 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and recrystallized from acetonitrile. The crystals were isolated and dried under vacuum at 65° C. to afford 0.35 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 186-188° C.
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6]N=C=NCC.N[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1.C(O)(=[O:35])C=C>CN(C)C=O>[Cl:31][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][C:23]([NH:3][C:4](=[O:35])[CH:5]=[CH2:6])=[CH:14][CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: C=CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2c(Nc3cccc(Cl)c3)ncnc2c1
Temperature: 0 °C
Yield: 20.3 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol) was added to a solution of 6-amino-4[(3-chlorophenyl)amino]quinazoline (136 mg, 0.5 mmol) and acrylic acid (108 mg, 1.5 mmol) in dimethylformamide (DMF) (5 mL), stirred under nitrogen at 0° C. After 15 minutes the reaction mixture was stirred at 25° C. for 18 hours, and then poured onto ice-water (50 mL) and after 1 hour the precipitate was collected by Buchner filtration. The residue was rinsed, air dried, dissolved in the minimum of 25° C. methanol (MeOH) (60 mL), concentrated at 25° C. under reduced pressure to below 10 mL, and recrystallized at 0° C. to give N-[4-[(3-chlorophenyl)-amino]quinazolin-7-yl]acrylamide (33 mg, 20%) as a light orange solid, mp 296.5-298.5° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23]([NH:25][CH3:26])=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11].C[I:28]>C(O)C>[IH:28].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23](=[N:25][CH3:26])[S:24][CH3:1])[N:17]=1)[C:10]([NH2:12])=[NH:11]
Reactant: CI
Reactant: CNC(=S)NCCSCc1csc(NC(=N)N)n1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CN=C(NCCSCc1csc(NC(=N)N)n1)SC
Product: I

Procedure:
A solution of 2-guanidino-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole hydrogen maleate (0.42 g.) in ethanol (15 ml.) was treated with methyl iodide (0.175 g.). The clear solution was heated under reflux on a steam bath for 1.5 hours, cooled and the volume reduced to 5 ml. by evaporation under reduced pressure. The insoluble material was filtered and recrystallized from ethanol to give 2-guanidino-4-[2-(2,3-dimethylisothioureido)ethylthiomethyl]thiazole hydrogen maleate hydriodide. Found: C, 30.2; H, 4.1; N, 14.8; S, 17.2. C14H23IN6O4S3 requires C, 29.94; H, 4.09; N, 14.97; S, 17.11%