Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([C:14]1[C:22]2[C:17](=[C:18]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[N:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[C:5](OC)=[O:6].[BH4-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([C:14]1[C:22]2[C:17](=[C:18]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[N:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1c(Cl)cc(CO)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Temperature: 60 °C
Yield: 2.1 %

Procedure:
To a solution of methyl 3,5-dichloro-4-({7-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)benzoate (100 mg, 2.31 mmol) in 1,4-dioxane and water (3:1), sodium borohydride (27 mg, 6.944 mmol) was added portion wise over a period of about 15 minutes, followed by heating the reaction mixture at 60° C. until starting material was consumed (approximately 3 hours) The reaction mixture was cooled to room temperature and quenched by the addition of saturated aq. ammonium chloride solution and extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-{3-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropane carboxamide (20 mg, 22%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18]3[CH:19]=[CH:20][N:29]=[C:30]([NH2:32])[N:31]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CON=C1CCc2cc(-c3ccoc3C(=O)/C=C/N(C)C)ccc21
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CON=C1CCc2cc(-c3ccoc3-c3ccnc(N)n3)ccc21
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A solution of the product of Step 2 (0.30 g, 0.93 mmol) in 1,4dioxane (6 ml) was treated with a solution of guanidine carbonate (0.33 g, 1.86 mmol) and sodium hydroxide (0.1 7 g, 4.1 mmol) in water (2 ml). The mixture was heated at 100° C. for 4 hours. After cooling to room temperature, water was added and the mixture extracted into ethyl acetate (2×). The organic layers were combined and washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with dichloromethane and the resulting solid filtered to afford the title compound (200 mg, 67%); MS(ES+) m/e 321 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([N:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[C:30]([Cl:42])[CH:29]=3)[O:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:12]4[O:13][CH:14]5[CH2:15][NH:8][CH2:9][CH:10]5[N:11]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)OC(=O)N1CC2N=C(Nc3ccc4ncnc(Nc5ccc(OCc6ccccn6)c(Cl)c5)c4c3)OC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2ncnc3ccc(NC4=NC5CNCC5O4)cc23)ccc1OCc1ccccn1

Procedure:
N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]oxazole-5-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS APCI (+) m/z 488, 490 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CD3OD) δ 8.56 (d, 1H), 8.44 (s, 1H), 8.21 (br. s, 1H), 7.91 (m, 2H), 7.70 (m, 2H), 7.63 (d, 1H), 7.57 (d, 1H), 7.39 (m, 1H), 7.16 (d, 1H), 5.28 (s, 2H), 5.17 (m, 1H), 4.78 (m, 1H), 3.34 (d, 1H), 3.16 (d, 1H), 2.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][N:17]=1>CN1CCCC1=O.O>[Cl:12][C:13]1[S:14][C:15]([CH2:18][NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:16][N:17]=1
Reactant: Nc1nccc2ccccc12
Reactant: ClCc1cnc(Cl)s1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ncc(CNc2nccc3ccccc23)s1
Temperature: 220 °C
Yield: 10.9 %

Procedure:
A mixture of 1-aminoisoquinoline (0.56 g, 3.9 mmol) and 2-chloro-5-(chloromethyl)thiazole (0.50 g, 3.0 mmol) in N-methylpyrrolidinone (3 mL) was heated to 220° C. in a microwave reactor for 10 min. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with diethyl ether (5×20 mL). The combined organic extracts were concentrated under reduced pressure, and the resulting residue was purified by chromatography on silica gel eluted with 20-50% ethyl acetate/hexane to give the title compound as a pale yellow solid (0.09 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2]>C(O)(=O)C.O.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([C:13]#[N:14])[CH:9]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a suspension of 3-(4-cyano-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (1.21 g, 4.62 mmol) in acetic acid (50 mL) and water (8 mL) add zinc powder (1.81 g, 27.7 mmol) portionwise over 2 h. Stir at rt for 3 h then filter to remove the solids. Concentrate the filtrate to a volume of 10 mL, dilute with EtOAc (40 mL), and filter again to remove insoluble material. Concentrate the filtrate to give the desired product 6-cyano-1H-indole-2-carboxylic acid ethyl ester as a solid (670 mg, 3.13 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([N:15]1[CH2:19][CH2:18][C@@H:17](O)[CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:27])CC>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([F:27])[CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CC[C@@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a mixture of S)-2-((R)-3-hydroxy-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 2.8 mmol) in dichloromethane (5 mL) at −78° C., was added slowly DAST (0.4 mL, 3 mmol). After stirring at room temperature for 3 h, the reaction mixture was diluted with methanol and concentrated. The residue was dissolved in EtOAc and washed with sodium bicarbonate solution (3×), sodium chloride (1×). After concentrating, the residue was purified to give 700 mg (87%) of (S)-2-((R)-3-fluoro-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26](=[O:27])[O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cnn(CCN3CCCC3)c2c1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (0.220 g, 0.955 mmol) and triethylamine (0.240 mL, 1.72 mmol) in 1 mL of THF at 0 C was slowly added phenyl chloroformate (0.246 ml, 1.72 mmol). The mixture was stirred cold for 1 hours and the formed precipitate collected by filtration with rinsing with ether to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.97 (m, 2 H), 2.97 (m, 2 H), 3.49 (m, 2 H), 3.69 (m, 2 H), 4.71 (t, J=6.27 Hz, 2 H), 7.19 (m, 1 H), 7.28 (m, 3 H), 7.46 (m, 2 H), 7.74 (m, 1 H), 7.99 (m, 1 H), 8.10 (s, 1 H), 10.51 (s, 1 H); MS (DCI/NH3) m/z 351 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]=[N+:19]=[N-:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl>[N:18]([S:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[CH:14][CH:13]=1)(=[O:16])=[O:17])=[N+:19]=[N-:20]
Reactant: O=C1C=CC(=O)O1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(NC(=O)/C=C\C(=O)O)cc1
Reaction time: 2 h

Procedure:
100 g maleic acid anhydride are dissolved in 1 liter dichloromethane and to this solution are added drop-wise 198 g of the 4-aminobenzenesulfonylazide (approximately 1 mol) prepared according to (3), dissolved in 400 ml dichloromethane. The reaction mixture is left standing for 2 hours at room temperature. The solution is then concentrated in a rotary evaporator to about 200 ml. The light brown product obtained is cooled, filtered, washed with a small amount of dichloromethane and finally dried.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C)n2)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)n2)cc1
Yield: 33.1 %

Procedure:
Using cyclohexyl[1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.68 g) synthesized in Example 23(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.42 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.28 g, 24%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].C1(C)C=CC(S([CH2:36][N+:37]#[C-:38])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([C:20]2[O:21][CH:38]=[N:37][CH:36]=2)[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C=O)nc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2cnco2)nc(N)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 64.1 %

Procedure:
(2-Amino-6-formyl-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (190 mgs/0.529 mmols) was dissolved in MeOH (5 mls). Added (4-tolylsulphonyl)methylisocyanide (124 mgs/0.634 mmols) followed by anhydrous potassium carbonate (200 mgs/1.45 mmols). Stirred under N2 for 1 hr then concentrated in vacuo. Partitioned between EtOAc (100 mls) and H2O (50 mls). Organic collected, washed with brine, dried over Na2SO4, filtered and concentrated to a black resin. Purification by column chromatography eluting with 90:10 DCM/MeOH gave the title compound (135 mgs) as a crude brown solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[OH-].[K+]>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH:13]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
A solution of 6-fluoroindole (2 g, 15 mmol) and 4-piperidone (3 g, 19.6 mmol) in 2 N solution of KOH in MeOH (60 mL) was stirred at reflux for 72 h. The mixture was concentrated to ¼ volume, diluted with H20 and filtered affording 2.5 g (77%) as a pale yellow solid: mp 202-204° C.; MS (APCI) m/z 217 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.[Mg].[CH:12](=[O:15])[CH2:13][CH3:14].O>O1CCCC1>[OH:15][CH:12]([CH2:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: ClCCCCC1C=CCC1
Reactant: CCC=O
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)CCCCC1C=CCC1
Temperature: 0 °C

Procedure:
All reactions are carried out under an inert atmosphere. 3-(4-Chlorobut-1-yl)cyclopentene {3-(4-chlorobutyl)cyclopentene} (43 g, 0.27 moles) is diluted in tetrahydrofuran (50 ml) and added dropwise to a stirred, refluxing solution of tetrahydrofuran (200 ml) containing granular magnesium (30 g, 1.25 moles). After the addition is complete and the resulting Grignard salt has formed the reaction is refluxed an additional 2 hours. The reaction vessel is then cooled in a 0° C. ice bath and propionaldehyde (15.6 g, 0.27 moles) diluted in tetrahydrofuran (20 ml) is added dropwise over 30 minutes. Then water (500 ml) is added over a period of 30 minutes and the reaction warmed to room temperature. The reaction is partitioned between ether (500 ml) and water. The aqueous layer is extracted with ether (2×500 ml) and the organic extracts are combined. The product is washed with brine (500 ml) and the solvent volume reduced under vacuum. The residue is dried over anhydrous magnesium sulfate and the solid filtered out. The remaining solvent is removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving the desired product as a clear, colorless oil (52 g, 0.29 moles), BP 76° C./0.25 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].CCN(CC)CC.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[C:2]1([CH3:1])[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH:8][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: Cc1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of o-tolylamine (21 g, 0.20 mol) and Et3N (22 g, 0.22 mol) in CH2Cl2 was added 2,2-dimethyl-propionyl chloride (25 g, 0.21 mol) at 10° C. After addition, the mixture was stirred overnight at room temperature. The mixture was washed with aq. HCl (5%, 80 mL), saturated aq. NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give N-o-tolylpivalamide (35 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.2 Hz, 1H), 7.15-7.25 (m, 2H), 7.05 (t, J=7.2 Hz, 1H), 2.26 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [NH2:1][C:2](=[O:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1.[Br:18]Br>C(Cl)(Cl)Cl>[NH2:1][C:2](=[O:17])[CH2:3][O:4][C:5]1[C:14]([Br:18])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1
Reactant: COC(=O)c1ccc(OCC(N)=O)cc1OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(OCC(N)=O)cc1OC
Temperature: 0 °C
Yield: 104 %

Procedure:
To a 250 mL round-bottomed flask was added methyl 4-(2-amino-2-oxoethoxy)-2-methoxybenzoate (1.2 g, 5.14 mmol) and chloroform (40 mL). The mixture was placed under a nitrogen atmosphere and cooled to 0° C. Bromine (0.263 mL, 5.14 mmol) was added drop wise (in 3 mL of chloroform) and the solution was allowed to warm to room temperature overnight. The orange solid was cooled with an ice bath, filtered, washed sequentially with cold chloroform, then diethyl ether. The product was dried under vacuum giving 1.7 grams (91% yield) of methyl 4-(2-amino-2-oxoethoxy)-5-bromo-2-methoxybenzoate as an orange solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 3.76 (s, 3H), 3.88 (s, 3H), 4.63 (s, 2H), 6.76 (s, 1H), 7.10 (br. s., 2H), 7.96 (s, 1H). LCMS Rt=1.793 min., m/z 319.1 (M+H), 90% purity.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:35]=[CH:34]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:42]2[CH2:43][CH2:44][N:39]([C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[C:29]([O:28][CH3:27])[CH:30]=[CH:31][CH:32]=4)[N:37]=3)[CH2:40][CH2:41]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1cccc2ccc(N3CCNCC3)nc12
Product: COc1cccc2ccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)nc12

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-methoxy-2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:7][C:2]=1[CH3:1])(=[O:10])[CH3:11]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(C)=O)c(C)c1
Reaction time: 48 h

Procedure:
A mixture of 4-hydroxy-2-methylacetophenone (4.8 g), anhydrous potassium carbonate (5.3 g) and methyl bromoacetate (3.55 ml) in anhydrous acetone (100 ml) was stirred for 2 days. The mixture, after filtration and evaporation of the solvent, gave methyl 4-acetyl-3-methylphenoxyacetate, 6.6 g, as a crystalline solid: m.p. 49°-50° C.; NMR (d6DMSO) δ7.84 (1H, d), 6.83 (2H, m), 4.87 (2H, s), 3.71 (3H, s), 2.50 (3H, s), 2.45 (3H, s).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:27])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH3:22])[C:18]([CH2:23][CH2:24][O:25][CH3:26])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:51]>C(Cl)(Cl)Cl>[CH:1]([NH:4][C:5](=[O:27])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH3:22])[C:18]([CH2:23][CH2:24][O:25][CH3:26])=[N:17][C:12]=3[C:13]([NH2:51])=[N:14][C:15]=2[CH:16]=1)([CH3:3])[CH3:2]
Reactant: CCCn1c(CCOC)nc2cnc3cc(OC(=O)NC(C)C)ccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC(=O)NC(C)C)ccc3c21
Reaction time: 1.5 h

Procedure:
2-(2-Methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl isopropylcarbamate (1.89 g, 5.10 mmol) was dissolved in chloroform (41 mL). 3-Chloroperoxybenzoic acid (60% pure, 1.60 g, 5.56 mmol) was added in one portion. After 30 minutes the golden solution was diluted with ammonium hydroxide (41 mL), and p-toluenesulfonyl chloride (0.927 g, 4.86 mmol) was added. The reaction was stirred for 1.5 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid residue was recrystallized from acetonitrile to provide 0.986 g of 4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl isopropylcarbamate as a granular, peach-colored solid, mp 144.0-146.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2ccc3ccn(-c4ccnc(N)n4)c3c2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
4-(6-(3-Nitrophenyl)-1H-indol-1-yl)pyrimidin-2-amine (76.8 mg, 0.232 mmol) was dissolved in ethanol and, after adding SnCl2.2H2O (262 mg, 1.159 mmol), the mixture was stirred at 100° C. for 3 hours. The reaction mixture was added to sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, MC:MeOH=20:1) yielded 4-(6-(3-aminophenyl)-1H-indol-1-yl)pyrimidin-2-amine (42 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3]1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CO
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl

Procedure:
In analogy to the procedure described for example 1 b], [2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol (example 3 b]) was reacted with thionyl chloride in chloroform to yield 5-chloromethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=O)=[CH:4][C:3]=1[CH3:12].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:24][C:25]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl>[Br:34][C:31]1[CH:30]=[C:26]2[C:25](=[CH:33][CH:32]=1)[N:24]=[C:6]([C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH3:12])[CH:4]=1)[NH:29][C:27]2=[O:28]
Reactant: NC(=O)c1cc(Br)ccc1N
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(Br)cc3c(=O)[nH]2)cc(C)c1O
Reaction time: 1.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzoic acid (2.00 g, 12.0 mmol) in CH2Cl2 (60.2 mL) cooled to 0-5° C. was added oxalyl chloride (1.47 mL, 16.8 mmol) followed by dropwise addition of DMF (93.3 μL, 1.20 mmol). The mixture was stirred for 1.25 h, the volatiles were removed under vacuum to give crude acid chloride, which was used immediately without further purification. A mixture of 2-amino-5-bromobenzamide (1.99 g, 9.23 mmol) and the acid chloride (crude residue described above) in THE (92.3 mL) was stirred at room temperature for 17 h, then heated at reflux for 4 h. The volatiles were removed under vacuum, the residue was triturated with EtOAc, and filtered to afford the amide (3.02 g, 90%) as a yellow solid. A mixture of the amide (3.01 g, 8.29 mmol), 2 M NaOH (20.0 mL), water (40.0 mL), and MeCN (20.0 mL) was heated at reflux for 15 h, cooled to 5° C., and neutralized with 2 M aqueous HCl. After stirring for 30 min, the white solid was filtered, triturated with acetone, and filtered again to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.28 g, 80%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=2.29 Hz, 1H), 7.93 (dd, J=8.72, 2.42 Hz, 1H), 7.86 (s, 2H), 7.63 (d, J=8.70 Hz, 1H), 5.75 (s, 1H), 2.24 (s, 6H); MS (APCI) m/z 346 [M+H]+.