Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][C:16]([C:23]([OH:25])=[O:24])=[C:15]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1.O>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][C:16]([C:23]([O:25][CH2:7][CH3:8])=[O:24])=[C:15]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: COc1ccc(-c2c(C(=O)O)[nH]c3cc(OC)c(OC)cc23)cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Potassium carbonate (0.139 g) and ethyl iodide (0.13 ml) were added to a solution of 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (0.3 g) in N,N-dimethylformamide (5 ml). The mixture was stirred for 3 hours at room temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give ethyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (0.272 g, 84%) as pale red prisms.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26].ClC1C=CC=C(C(OO)=[O:35])C=1>>[OH:1][CH2:2][CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13](=[O:35])[C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c2cccc3c2n(c(=O)n1CCO)-c1cc(C(F)(F)F)ccc1S3
Product: O=c1c2cccc3c2n(c(=O)n1CCO)-c1cc(C(F)(F)F)ccc1S3=O

Procedure:
When 2-(2-hydroxyethyl)-10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione was oxidized with m-chloroperbenzoic acid as described in the procedure of Example 6, the title compound was obtained, m.p. 205-206° (ethanol).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[C:14]2([CH2:17][CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[C:8]([CH3:20])[C:9]([OH:19])=[C:10]([CH3:18])[CH:11]=2)[CH:6]=1.Cl>C1COCC1.O1CCOCC1>[CH3:1][O:2][NH:3][CH2:4][C:5]1[C:14]2([CH2:15][CH2:16][CH2:17]2)[O:13][C:12]2[C:7](=[C:8]([CH3:20])[C:9]([OH:19])=[C:10]([CH3:18])[CH:11]=2)[CH:6]=1
Reactant: CON=CC1=Cc2c(cc(C)c(O)c2C)OC12CCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CONCC1=Cc2c(cc(C)c(O)c2C)OC12CCC2
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutane]-3-carbaldehyde O-methyloxime (150 mg) in 10 mL of THF at 0° C. was added BH3/pyridine complex (2.27 mL). Subsequently, 9 mL of HCl in dioxane (4.0 M solution) was added over a period of 1 hour. The reaction mixture was allowed to stir overnight. The mixture was extracted with ethyl acetate, washed with saturated NaHCO3, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 30% ethyl acetate in hexane to give 142 mg of 3-[(methoxyamino)methyl]-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-6-ol as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=6.59 (s, 1H, =CH), 6.45 (s, 1H), 5.50 (b, 1H), 4.75 (b, 1H), 3.81 (s, 2H), 3.62 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 2.40-1.75 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=146.3, 146.0, 134.0, 123.9, 120.3, 119.4, 119.1, 114.6, 81.1, 62.0, 54.7, 33.1, 16.5, 14.3, 11.2 ppm. MS: (m/z)=229.1 (M−NH2OMe+).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCC(=O)NC1CCCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as light grey foam in 86% yield. MS: 349.2 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:2]1.Cl.Cl.Cl.[N:23]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([NH:38][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:36][CH2:37]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (preparation see below) and amine 5.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:12])[NH:7]3)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(CCCCBr)c1ccccc1
Reactant: O=C1CCc2c(O)cccc2N1
Product: O=C1CCc2c(cccc2OCCCCS(=O)c2ccccc2)N1

Procedure:
Prepared analogous to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylsulfinyl-butyl bromide.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>>[C:12]([C:15]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[NH:1][C:16]=1[CH3:17])(=[O:14])[CH3:13]
Reactant: N#CC(N)c1ccc(F)cc1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)c1c(C)[nH]c(-c2ccc(F)cc2)c1N

Procedure:
Starting from 2-amino-2-(p-fluorophenyl)acetonitrile and acetylacetone, the open-chain intermediate compound is obtained; b.p. 150° C./0.3 mm Hg. Overall yield of the title compound: 47%, m.p. 211°-12° C. (from ethanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][CH2:40][O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][CH2:39][CH2:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCOC1CCCCO1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2cnn(CCCOC3CCCCO3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.02 g) and 1-bromo-3-(2-oxanyloxy)propane (0.45 mL) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(2-oxanyloxy)propyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.65 g) was obtained. This compound was dissolved in methanol (30 mL), and 4 mol/L-HCl/dioxane (0.1 mL) was added. The mixture was stirred at room temperature for 2 hr. Into the reaction mixture was poured saturated aqueous sodium hydrogencarbonate (2 mL). The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated. By the reaction and treatment of the obtained residue (0.94 g) in the same manner as in Example 105, 5-hydroxy-N-{[1-(3-hydroxypropyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].II.[Br:22]Br>C(O)(=O)C.O>[C:1]([O:4][C:5]1[CH:12]=[C:11]([Br:22])[C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COc1cc(C=O)ccc1OC(C)=O
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=O)c(Br)cc1OC(C)=O
Temperature: 45 °C

Procedure:
To a mixture of 4-acetoxy-3-methoxybenzaldehyde (75.7 g), anhydrous sodium acetate (76 g) and iodine (0.8 g) in acetic acid (300 ml) is added bromine (21 ml). The mixture is warmed to 45° C. for about 1 hour, then stirred stirred at room temperature for 3 days, poured into water (700 ml) and filtered. The solid is dissolved in toluene and the solution washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is recrystallized twice from hexanes to give the desired product.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].C[O-].[Na+].[F:12][C:13]1[CH:14]=[C:15]([C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].Cl>C(OC)(C)(C)C>[F:1][CH:2]([F:8])[C:3](=[O:4])[CH2:22][C:21]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([F:12])[CH:14]=1)=[O:23]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1ccc(C(=O)CC(=O)C(F)F)cc1F
Reaction time: 16 h

Procedure:
Ethyl difluoroacetate (4.06 g, 32.7 mmol) was dissolved in methyl tert-butyl ether (50 mL). To the stirred solution was added 25 weight % sodium methoxide (7.07 g, 32.7 mmol) followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (5.0 g, 29.7 mmol). After stirring for 16 hours, 1N HCl (50 mL) was added. The organic layer was collected and washed with water (2×50 mL), dried over anhydrous MgSO4, filtered, and added to hexanes to precipitate a tan solid (7.0 g, 96%): mp 70-72° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1>C(Cl)Cl.CC(N(C)C)=O>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of acryloyl chloride (0.604 mL, 1M in CH2Cl2, 0.60 mmol) was added dropwise to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine (Intermediate 164, 268 mg, 0.60 mmol) in CH2Cl2 (10 mL) and 10 mL DMA, which was cooled to −5° C. The resulting mixture was stirred at −5° C. for 1 h and was then diluted with CH2Cl2 (100 mL). The resulting solution was washed with sat. NaHCO3 (25 mL), water (25 mL), and then sat. brine (4×25 mL), and was then concentrated in vacuo. Purification by FCC, eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (135 mg, 45%) as a beige solid; 1H NMR (CDCl3) 1.98 (1H, s), 2.18 (1H, d), 2.94 (1H, s), 3.11 (4H, d), 3.88 (3H, s), 5.73 (1H, d), 6.40 (2H, d), 6.76 (1H, s), 7.17 (1H, d), 7.22-7.24 (1H, m), 7.41-7.46 (1H, m), 7.62 (1H, s), 8.16 (1H, s), 8.39 (1H, d), 8.45 (1H, s), 8.75 (1H, s), 8.86 (1H, s), 9.56 (1H, s); m/z: ES+ MH+ 498.
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][C:25]([CH3:38])([CH2:36][CH3:37])[C:26](=[O:35])[C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][NH:30]1)=[O:28]>>[C:1]([N:30]1[CH:29]([C:27](=[O:28])[C:26](=[O:35])[C:25]([CH3:38])([CH3:24])[CH2:36][CH3:37])[CH2:34][CH2:33][CH2:32][NH:31]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1
Reactant: C#CCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a solution of 5-hexynoic acid (0.467 g, 4 mmol) in 10 ml CH2Cl2was added triethylamine (0.56 ml, 4 mmol), followed by isobutyl chloroformate (0.53 ml, 4 mmol) at 0° C. After stirring for 5 minutes, a solution of 3,3-dimethyl-1-perhydropyridazinyl pentane-1,2-dione (0.424 g, 2 mmol) in 1 ml CH2Cl2was added. The reaction was gradually warmed up to room temperature. The crude material was subject to silica gel purification to yield final product as clear oil (0.385 g, 63%). 1H NMR (CDCl3, 400 MHz): δ 0.91 (t, 3H, J=7.0); 1.26 (s, 6H); 1.76(m, 8H); 2.28 (m, 2H); 2.50 (m, 2H); 2.88 (m, 2H); 3.60 (m, 1H); 4.50 (m, 2H).
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[C:7]([CH2:16][NH2:17])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)([O-])=O>[Pd].CCO.CO>[NH2:17][CH2:16][C:7]1[C:6]([NH2:3])=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: NCc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: NCc1ccc2cccnc2c1N
Reaction time: 5 h
Yield: 2.6 %

Procedure:
Palladium on Carbon (5%, 25 mg) was added to a solution of C-(8-nitroquinolin-7-yl)-methylamine dihydrochloride (Intermediate 210) (180 mg, 1.09 mmol) in EtOH (10 ml) and the mixture was stirred under an atmosphere of hydrogen for 5 h. The mixture was diluted with MeOH (10 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (5 mg, 31%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])([O-:7])=[O:6]>>[CH:3]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])=[CH:2][CH3:1]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=CCBr
Product: CC=COc1ccccc1[N+](=O)[O-]

Procedure:
Allyl bromide was reacted with o-nitrophenol to yield 2-prop-1-en-oxynitrobenzene; which was reduced to the corresponding aniline; then reacted with 5-methyl-N-chloromethyl-2-pyrrolidone to form the corresponding 5-methyl-N'-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CN
Product: CNCc1cccc(Br)n1

Procedure:
The title compound was prepared according to the procedure in Example 45 Step 1 using 6-bromopyridine-2-carbaldehyde (0.50 g, 2.69 mmol) and methylamine (0.253 mg, 2.69 mmol) as the starting materials
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.Cl.N([O-])=O.[Na+].[I-:20].[Na+]>O>[I:20][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: [I-]
Reactant: COC(=O)c1cc(N)c2cc[nH]c2c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(I)c2cc[nH]c2c1
Yield: 16.2 %

Procedure:
To a mixture of methyl 4-amino-1H-indole-6-carboxylate (Example SP-216, step 3) (3.2 g) in water (50 mL) was added concentrated hydrochloric acid (5 mL). The mixture was chilled to below 5° C. with the addition of ice. To this was added sodium nitrite (1.16 g) dissolved in water (10 mL). The mixture was stirred chilled for 1 h followed by addition of sodium iodide (3 g) in water (20 mL). The mixture was stirred for 30 minutes, filtered and the solids collected by filtration were washed with water and dried at 50° C. The solids turned black and gas evolved rapidly upon drying. Column chromatography on silica gel (200 mL) using 20% hexanes in CH2Cl2 as eluent to give 0.82 g of the title compound: 1H NMR (CDCl3) δ 3.94, 6.55, 7.43, 8.14, 8.22, 8.62.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.C(N(CC)CC)C>C1COCC1>[Cl:9][C:10]1[N:15]=[C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under external cooling with ice, 2.22 g (20.0 mmol) 4-fluoroaniline is added dropwise to a solution of 4.46 g (23.0 mmol) 2,4-dichloro-5-nitropyrimidine in 20 ml THF. Then a solution of 2.77 ml (20.0 mmol) triethylamine in 5 ml THF is added slowly under external cooling with ice. The reaction mixture is stirred for 1 hour at room temperature. The precipitate is filtered off and washed with THF. The filtrate is evaporated and crystallized from tert-butyl-methylether giving (2-chloro-5-nitro-pyrimidin-4-yl)-(4-fluoro-phenyl)-amine as yellow crystals; HPLC/MS (B): 2.26 min, [M+H] 269;
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4].[C:25](O)(=[O:27])[CH3:26]>C(OC(=O)C)(=O)C>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][C:25](=[O:27])[CH3:26])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCNc1cc(CNC(C)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g; prepared as described in Example 289) in acetic acid (10 ml), acetic anhydride (0.4 ml) is added and the mixture is left for 24 hours. Dilution with water (25 ml) precipitates N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)acetamide, which is collected by filtration, washed with water and dried in air. After recrystallization from aqueous ethanol it is obtained with a melting point of 190°-191° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[C:15]3[N:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH2:17][C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[Br:1][C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:16]2[C:15]=1[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[NH:19][C:18](=[O:20])[CH2:17]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cn2c(c(Br)c3ccccc32)-c2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 2.36 g N-bromosuccinimide in 50 ml dimethylformamide was added dropwise to a solution of 3.0 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml dimethylformamide, during which the reaction mixture was cooled with cold water. The resulting solution was stirred at room temperature for two hours and then poured into 800 ml water. The precipitate was collected, washed with water and dried under vacuum (P2O5) to give 3.7 g solid;
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][O:32][CH2:33][CH3:34])[N:14]([CH2:15][C:16]3[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:5][C:4]=2[N:3]=1>Cl>[NH2:21][CH2:20][C:19]1[CH:29]=[CH:30][C:16]([CH2:15][N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][C:6]([C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[CH:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:31][O:32][CH2:33][CH3:34])=[CH:17][CH:18]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CN)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
tert-Butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}carbamate (0.660 g) was added to ethanolic hydrogen chloride (4M, 10 mL) and the solution was heated at reflux temperature for 30 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. Diethyl ether and water were added to the oily residue and the layers were separated. The aqueous fraction was brought to pH 13 with 10% aqueous sodium hydroxide and then extracted sequentially with dichloromethane and dichloromethane containing 5% methanol. The organic fractions were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 0.526 g of 1-(4-aminomethylbenzyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 211.0–213.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].CCN(CC)CC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>CN(C=O)C>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11]2)=[C:2]([NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1cc(C#N)ccc1C1CCc2cncn21

Procedure:
A DMF (3 mL) solution of 3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.095 g, 0.42 mmol), given as example 6B, is treated with Et3N (0.09 mL, 0.64 mmol) and butyryl chloride (0.05 mL, 0.51 mmol) at room temperature. After 1 h the solution is concentrated. Purification via prep HPLC gives N-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-phenyl]-butyramide. MS (ESI) m/z 295.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (t, J=7.3 Hz, 3 H), 1.67-1.80 (m, 2 H), 2.35 (t, J=7.5 Hz, 2 H), 2.49-2.61 (m, 1 H), 2.88-3.01 (m, 2 H), 3.05-3.18 (m, 1 H), 5.56 (dd, J=8.0, 5.9 Hz, 1 H), 6.84 (s, 1 H), 6.97 (d, J=8.1 Hz, 1 H), 7.40 (s, 1 H), 7.45 (dd, J=8.1, 1.5 Hz, 1 H), 7.70 (br s, 1 H), 7.91 (s, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[S:15]2)=[C:6]([CH2:35][CH2:36][CH3:37])[C:5]=1[OH:38])(=[O:3])[CH3:2].[OH-].[Li+]>C(O)C>[C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[S:15]2)=[C:6]([CH2:35][CH2:36][CH3:37])[C:5]=1[OH:38])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2COC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCSCC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
The product of Example 2 (3 g, 0.0052 mol) was dissolved in ethanol (50 ml). Aqueous lithium hydroxide solution (2M, 9.2 ml) was added and the reaction solution was stirred at room temperature for 3 hrs. Ethanol was removed using the rotary evaporator and the aqueous residue was acidified to pH2 using aqueous 0.5N sodium bisulfate solution. The oil which separated was extracted with ethyl acetate and the organic layer dried over anhydrous magnesium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 2.53 g of a colorless oil which was dried at 70° (0.1 mm Hg) for 5 hrs to give the title compound.