Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1.C=O.[C:14](O)(=O)C>O.CO>[CH3:11][N:2]([CH3:1])[C:3]1[S:4][C:5]2[CH2:14][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: CN(C)c1nc(CCN)cs1
Agent: C=O
Solvent: CO
Solvent: O
Product: CN(C)c1nc2c(s1)CNCC2
Reaction time: 2.5 h
Yield: 219.2 %

Procedure:
2-Dimethylamino-4-(2-aminoethyl)thiazole (1.7 g, see preceding preparation), formaldehyde (0.78 ml of a 37% solution in water, 9.6 mmol) and acetic acid (0.15 ml, 2.6 mmol) were combined in methanol (100 ml). After 2.5 hours at room temperature, the reaction mixture was treated with additional formaldehyde (0.15 ml, 1.8 mmol) and allowed to stir for an additional 16 hours. The reaction was then filtered, and the filtrate was concentrated in vacuo and purified by column chromatography (eluant: 89:10:1 of chloroform:methanol:concentrated ammonium hydroxide), providing the title product as a white solid (1.04 g, 5.7 mmol).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Cl.C[O-].[Na+].N[C:10]1[C:15]([C:16]#[N:17])=[CH:14][C:13]([C:18]#[N:19])=[CH:12][N:11]=1.C1CCCCC1.CCOC(C)=O>CCO>[NH2:3][C:2]1[N:4]=[C:16]([NH2:17])[C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[N:11][C:10]=2[N:1]=1
Reactant: N=C(N)N
Reactant: N#Cc1cnc(N)c(C#N)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cnc2nc(N)nc(N)c2c1
Yield: 34 %

Procedure:
Guanidine·HCl (2.66 g, 27.8 mmol) was added to a solution of NaOMe (sodium methoxide) (1.50 g, 27.8 mmol) in absolute EtOH (180 mL). The mixture was stirred at 20°-23° C. for 15 minutes before 5 (2.00 g, 13.9 mmol) was added. After a 24-hour reflux period with rapid stirring, TLC (cyclohexane-EtOAc, 1:1) showed absence of 5. The solid filtered from the cooled mixture was washed on the funnel with H2O and EtOH; yield 95% (2.45 g). A sample of this material (1.0 g) was stirred with near-boiling Me2SO (dimethyl sulfoxide) (250 mL), and the slightly cloudy solution was filtered (Celite) to give a clear, pale-yellow filtrate which was then concentrated by evaporation in vacuo (to about 60 mL). Addition of EtOH (200 mL) gave 7 as a light yellow solid (880 mg); 1H NMR (Me2SO-d6) δ6.97 (2, NH2), 7.84 (s, NH2), 8.87 and 8.91 (two d, 5-H and 7-H, J=2 Hz).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Sc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Clc1nc(Cl)nc(Cl)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfophenylthio)anthraquinone-2-sulfonic acid (23.7 parts) and cyanuric chloride (9.3 parts) were subjected a to condensation reaction at 10° to 20° C. in an aqueous medium under a weak acid condition, followed by a condensation reaction with 1-aminobenzene-3-β-sulfatoethylsulfone (14.1 parts) at 20° to 30° C. under a weak acid condition. Thereafter, salting out of the reaction mixture gave an anthraquinone compound of the following formula (free acid form). ##STR426##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[S:36]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[NH:34][C:35]3=[S:36])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(CC3CCN(CCn4c(=S)[nH]c5ccccc54)CC3)nc3ccccc32)cc1
Yield: 41.5 %

Procedure:
A mixture of 6 parts of N1 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,2-benzenediamine, 2.7 parts of 1,1'-thiocarbonylbis[1H-imidazole] and 90 parts of tetrahydrofuran was stirred and refluxed for 1 hour. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was stirred in acetonitrile. The product was filtered off and crystallized from ethanol. The product was filtered off and dried, yielding 2.8 parts (41.5%) of 1-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H- benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazole-2-thione; mp. 157.1° C. (493).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C[OH:10].[CH3:11][NH:12][C@@H:13]1[CH2:22][C:21]2[C:16]3=[C:17]([NH:23][C:24](=[S:25])[N:15]3[CH2:14]1)[CH:18]=[CH:19][CH:20]=2>C(Cl)Cl>[C:1]([OH:8])(=[O:7])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10].[CH3:11][NH:12][C@@H:13]1[CH2:22][C:21]2[C:16]3=[C:17]([NH:23][C:24](=[S:25])[N:15]3[CH2:14]1)[CH:18]=[CH:19][CH:20]=2
Reactant: CO
Reactant: O=C(O)/C=C\C(=O)O
Agent: CN[C@@H]1Cc2cccc3[nH]c(=S)n(c23)C1
Solvent: ClCCl
Product: O=C(O)CC(O)C(=O)O

Procedure:
A mixture of maleic acid (0.317 g, 2.36 mmol) in a minimal amount of methanol (˜1 mL) is added to a mixture of (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (EXAMPLE 8, 0.493 g, 2.25 mmol) in methylene chloride. The resulting solid is collected by filtration to give the title compound, mp=195-196°; [α]25D=−60° (c 0.93, methanol); IR (drift) 3140, 3112, 3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389, 1361, 1220, 868 and 747 cm−1; NMR (300 MHz, CD3OD) 7.20-7.30, 7.10-7.20, 6.26, 4.49, 4.31, 4.05-4.20, 3.47, 3.28 and 2.83 δ; CMR (100 MHz, DMSO-d6+CD3OD) 170.4, 169.4, 136.6, 131.1, 130.9, 125.1, 122.1, 116.2, 109.6, 53.9, 43.1, 31.9 and 27.2 δ; MS (ESI, m/z) 220.1 (MH+).
Reaction SMILES: C1([N:4]2[C:13]3[C:8](=[CH:9][C:10](F)=[C:11](N4CCNCC4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)CC1.BrCC(OCC)=O.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.O>[O:21]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][CH:5]=[C:6]1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: CCOC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
3.3 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in 50 ml of dimethylformamide are heated at 90° C. with 2.5 g (0.015 mole) of ethyl bromoacetate, 2.1 g (0.02 mole) of triethylamine and 2.5 g of potassium iodide for 5 hours. The reaction mixture is poured into 30 ml of water and the precipitate is filtered off with suction, washed with water and recrystallised from methanol. 2.5 g of 1-cyclopropyl-6-fluoro-7-[4-ethoxycarbonylmethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 192° to 194° C. are obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[C:10]([C:12]1[N:16]([CH3:17])[C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)#N.C1([O:28]C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:17][N:16]1[C:12]([C:10]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)=[O:28])=[CH:13][CH:14]=[C:15]1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1CC(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Temperature: 110 °C
Yield: 86 %

Procedure:
To a solution of the Grignard reagent prepared from 0.71 g. (31 mmol) of magnesium and 5.3 g. (31 mmol) of 4-bromotoluene in 20 ml. of anhydrous tetrahydrofuran was added under an atmosphere of nitrogen a solution of 0.98 g. (6.0 mmol) of 5-cyano-1-methylpyrrole-2-acetic acid in 5 ml. of tetrahydrofuran. After the resulting yellow suspension was heated to the boiling point, 20 g. of diphenyl ether was added, and tetrahydrofuran was distilled from the reaction mixture until the temperature reached 110° C. The reaction mixture was then heated under reflux (110° C.) for 1.5 hours. During this time, the color of the suspension changed from yellow to dark orange. The reaction mixture was cooled and partitioned between ether and dilute aqueous hydrochloric acid. The ether phase was extracted with five percent aqueous sodium hydroxide solution, which was then acidified and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and concentrated to give 30 mg. of purple liquid which contained only a trace of starting cyanoacid by nmr analysis. The aqueous phase was heated in a steam bath for four hours, and the resulting suspension was cooled and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and concentrated to give 1.33 g. (86% yield) of 1-methyl-5-p-toluoyl-pyrrole-2-acetic acid as a brown solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[CH3:5]/[CH:6]=[CH:7]\[CH3:8].[CH3:9]/[CH:10]=C/C.C=C(C)C.C=CC=C.CCCC>C1C=CC=CC=1>[CH:2]([C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: C=CCC
Reactant: C/C=C/C
Reactant: C/C=C\C
Agent: C=C(C)C
Agent: C=CC=C
Solvent: CCCC
Solvent: c1ccccc1
Product: CCC(C)c1ccccc1
Reaction time: 72 h

Procedure:
A 0.5 gram sample of an MCM-49 catalyst (1.3 mm [ 1/20″] quadrulobe extrudate of 60% MCM-49/40% Versal 200 alumina binder, cut to 1.3 mm [ 1/20″] length) was used for the alkylation of benzene with a mixed butene feed having the following composition: 53.4% cis-butene, 41.2% trans-butene, 4.6% isobutene, 0.5% butadiene, 0.1% n-butane and 0.2% others. The catalyst was diluted with sand to 3 cc and loaded into an isothermal, down-flow, fixed-bed, tubular reactor having an outside diameter of 4.76 mm ( 3/16″). The catalyst was dried at 150° C. and 1 atm with 100 cc/min flowing nitrogen for 2 hours. The nitrogen was turned off and benzene was fed to the reactor at 60 cc/hr until the reactor pressure increased to 300 psig (2170 kPa). Benzene flow was then reduced to 7.63 cc/hr (6.67 WHSV) and the mixed butene feed was introduced from a syringe pump at 2.57 cc/hr. The reactor temperature was adjusted to 160° C. Feed benzene/butene molar ratio was maintained at 3:1 for the entire run. Liquid product was collected in a cold-trap and analyzed off line. Butene conversion was determined by measuring unreacted butene relative to feed butene. The MCM-49 was on stream for 3 days at 3.2 WHSV of butene with 96% conversion, 1 day at 9.6 WHSV with 80-83% conversion, and 3 days at 3.2 WHSV with 95% conversion. Relative activity of MCM-49 based on first-order butene conversion was 1.1. Representative data are shown in Table 1.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.[F:24][C:25]1[CH:26]=[C:27]([NH2:47])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[CH:38]=[C:39]([C:41]3[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=3)[S:40][C:33]=12.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:24][C:25]1[CH:26]=[C:27]([NH:47][C:4](=[O:6])[CH2:3][C:2]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:1])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[CH:38]=[C:39]([C:41]3[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=3)[S:40][C:33]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(O)CC(=O)Nc1cccnc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4cccnc4)cc3F)c2s1
Reaction time: 0.08 h

Procedure:
To a solution of the acid 39 (58 mg, 0.32 mmol) and HOBt (47 mg, 0.35 mmol) in DMF (5 mL), was added amine 9 (108 mg, 0.32 mmol). After stirring for 5 min, EDC (75 mg, 0.39 mmol) was added and the reaction mixture was stirred overnight at room temperature then poured into dilute NaHCO3 solution and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Aquasil C-18, gradient: MeOH in water 60% to 95%) to afford the title compound 40 as a white solid. (20 mg, 12%) 1H NMR (DMSO-d6) δ (ppm): 10.65 (s, 1H), 10.50 (s, 1H), 8.73 (d, 1H), 8.50 (d, 1H), 8.26 (dd, 1H), 8.05 (m, 1H), 7.88 (s, 1H), 7.87 (dd, 1H), 7.48 (t, 1H), 7.41 (m, 2H), 7.35 (m, 1H), 6.69 (d, 1H), 3.99 (s, 3H), 3.56 (s, 2H). MS (m/z): 503.1 (M+H).
Reaction SMILES: CC1CC[N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=CC=CC=3)[C:11]2=O)C1=O.O.NN.[CH2:25]1COCC1.CO>>[NH2:4][CH2:7][CH2:8][CH2:9][N:10]1[CH:11]([CH3:25])[CH2:12][CH2:17][C:18]1=[O:19]
Reactant: CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1=O
Reactant: C1CCOC1
Agent: NN
Solvent: CO
Solvent: O
Product: CC1CCC(=O)N1CCCN
Temperature: 50 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
2-[3-(3-Methyl-2-oxo-pyrrolidin-1-yl)-propyl]-isoindole-1,3-dione (0.5 g, 1.74 mmol) was taken in a mixture of THF/MeOH (3.0 mL/3.0 mL). Hydrazine hydrate (0.44 g, 8.7 mmol) was added to this and the reaction was stirred at 50° C. for 16 h. The precipitate was filtered and the filtrate was concentrated to give the product 1-(3-amino-propyl)-5-methyl-pyrrolidin-2-one (0.12 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[C:6]([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][CH:4]=1.[CH2:28](I)[CH3:29]>>[CH2:28]([N:10]1[C:9](=[O:17])[CH:8]2[CH:12]([CH2:13][CH2:14][C:15]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([O:18][CH2:19][CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:7]=32)[C:11]1=[O:16])[CH3:29]
Reactant: COc1ccc(OCCCc2ccccc2)c2c1CCC1C(=O)NC(=O)C21
Reactant: CCI
Product: CCN1C(=O)C2CCc3c(OC)ccc(OCCCc4ccccc4)c3C2C1=O

Procedure:
Using the procedure of example 64 with the product of example 135 and ethyl iodide gave the compound; M+ 393.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([S:12][CH3:13])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI>C(#N)C.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:16])[C:7]([S:12][CH3:13])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CSC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: CO
Product: CSC1=NS(=O)(=O)c2cc(Cl)ccc2N1C

Procedure:
A solution of 7-chloro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.8 g) in acetonitrile (24 mL) and methanol (0.5 mL) was supplemented with potassium carbonate (0.96 g), then with methyl iodide (3 mL), and stirred at room temperature for 10 h. The solvent was removed by distillation under reduced pressure. The residue was suspended in water (40 mL) and the pH was adjusted to pH 2 with formic acid. The precipitate of the title compound was collected by filtration, washed with water and dried. The compound was used without further purification in the next step (yield: 0.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=1)=[O:4].[CH2:18](I)[CH3:19].[H-].[Na+].Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH3:19])[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=1)=[O:4]
Reactant: CCI
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CCCC3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2c(c3cc(C(=O)OC)ccc31)CCCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1,2,3,4-Tetrahydrocarbazole-6-carboxylic acid methyl ester (460 mg) prepared by the method described in Journal of Chemical Society, p.809 (1926) was dissolved in 2.5 mL of DMF, and the solution was added with 0.3 mL of ethyl iodide and 120 mg of sodium hydride and stirred at room temperature at 50° C. for 2 hours under a nitrogen flow. Then, the reaction mixture was added with water, neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane) to obtain 490 mg of N-ethyl-1,2,3,4-tetrahydrocarbazole-6-carboxylic acid methyl ester.
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17](SC)=[NH:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:55][NH2:56]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:56][N:55]=[C:17]([NH:16][C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH:14]=[N:13][C:12]([CH3:15])=[N:11]3)=[C:4]([O:3][CH3:2])[CH:5]=2)[N:18]=1)[C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH3:38])=[CH:34][CH:35]=1
Reactant: CCOc1ccc(C(CCCCCl)C(=O)O)cc1
Reactant: NN
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(C)n1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Product: CCOc1ccc(C(CCCCCl)c2nc(Nc3ccc(-n4cnc(C)n4)c(OC)c3)n[nH]2)cc1

Procedure:
Methyl 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.500 g, 1.23 mmol), from preparation F) and 6-chloro-2-(4-ethoxyphenyl)hexanoic acid (0.367 g, 1.36 mmol, from preparation AAN) were coupled [N-methylmorpholine (0.678 mL, 6.17 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.155 mL, 4.94 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-ethoxyphenyl)pentyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 496.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]([OH:15])[CH3:14])=[CH:5][NH:6]2.[C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[CH2:17][CH2:18][CH3:19].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:16]1([CH2:17][CH2:18][CH3:19])[C:5]2[NH:6][C:7]3[C:3]([C:4]=2[CH2:12][CH:13]([CH3:14])[O:15]1)=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=3[F:11])[CH3:26]
Reactant: CC(O)Cc1c[nH]c2c(F)ccc(Br)c12
Reactant: CCCC(=O)CC(=O)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1(CC(=O)OCC)OC(C)Cc2c1[nH]c1c(F)ccc(Br)c21
Reaction time: 3 h

Procedure:
To a solution of 1-(4-bromo-7-fluoro-1H-indol-3-yl)-propan-2-ol (155 mg, 0.570 mmol) and ethyl butyrylacetate (0.137 mL, 0.854 mmol) in CH2Cl2 (3 mL) was added BF3.OEt2 (0.11 mL, 0.854 mmol) dropwise at room temperature. After stirring for 3 hours, the mixture was diluted with CH2Cl2 (15 mL) and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to give (5-bromo-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as a pale yellow solid (this sample contains ethyl butyrylacetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:17]1[N:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[N:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: Oc1ccc(Br)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 4-bromophenol (200 mg) in tetrahydrofuran were added triethylamine (193 μL) and 2-chloro-5-nitropyrimidine (204 mg). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL). The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the titled compound (294 mg) having the following physical data.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4Br)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.COCCNC1C=C(C=CN=1)C(NC1SC2C(N3CCOCC3)=CC=C(OC)C=2N=1)=O>>[O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[C:21]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:20]=4)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccncc3Br)nc12
Agent: COCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(N4CCCC4)c3)nc12

Procedure:
N-(7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-bromo-isonicotinamide and pyrrolidine were reacted as described for 2-(2-methoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown solid. MS: m/e=455(M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([CH:31]2[CH2:35][CH2:34][C:33]([CH3:37])([OH:36])[CH2:32]2)=[CH:29][CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1.O>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([CH:31]3[CH2:35][CH2:34][C:33]([CH3:37])([OH:36])[CH2:32]3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: CC1(O)CCC(c2cccnc2F)C1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(O)CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 180 °C

Procedure:
To a 20 mL microwave vial was added cesium carbonate (1460 mg, 4.48 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (565 mg, 2.331 mmol), and 3-(2-fluoropyridin-3-yl)-1-methylcyclopentanol (350 mg, 1.793 mmol) as a solution in NMP (3585 μL). The reaction mixture was heated to 180° C. for 3 h with microwave irradiation. The reaction was diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure to a dark brown oil. Three purifications of the diastereomeric mixture by SFC gave four compounds. MS (ESI, pos. ion) m/z: 418.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]([CH2:17][CH2:18][CH2:19][C:20]2([CH3:25])OCC[O:21]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:15])[C:6]=2[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[NH2:15][C:7]1[C:6]2[N:16]=[C:3]([CH3:2])[N:4]([CH2:17][CH2:18][CH2:19][C:20](=[O:21])[CH3:25])[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCC1(C)OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
Concentrated hydrochloric acid (3 mL) was added to 2-methyl-1-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol), and the mixture stirred for a few minutes until everything was in solution. Water (5 mL) was then added and the solution stirred for one hour at room temperature. After the addition of dichloromethane (75 mL) and water (25 mL), the solution was made basic by the slow addition of potassium carbonate (10.0 g). The layers were separated, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one, mp 194-196° C.