Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=O.[CH2:12]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][NH2:18])[CH2:13][CH2:14][CH3:15].CC(N)=NCC1C=CC=C(CN)C=1.Cl.Cl>CCCCCCC>[CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([NH:18][CH2:17][CH:16]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:6]
Reactant: CCCCCCC(CN)CCCC
Reactant: CC(CC(=O)O)CC(C)(C)C
Agent: CC(N)=NCc1cccc(CN)c1
Agent: Cl
Solvent: CCCCCCC
Product: CCCCCCC(CCCC)CNC(=O)CC(C)CC(C)(C)C
Yield: 76.6 %

Procedure:
29.2 g of 3,5,5-trimethylhexanoic acid and 34.2 g of 2-butyloctylamine were mixed together in an open Pyrex container and placed in a microwave oven (Menumaster™ 3100i; frequency 2450, power at a setting of 30%: 1400 W). After 6 irradiations of about 5 minutes (for each irradiation), the reaction mixture was dissolved in heptane and then purified on silica. 46 g (77%) of the desired amide were obtained.
Reaction SMILES: FC1C=C([C@@H](NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)C)C=CC=1F.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:40][C:41]1[CH:42]=[C:43]([C@@H:48]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58]4(OCC(C)(C)C[O:59]4)[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])[CH3:49])[CH:44]=[CH:45][C:46]=1[F:47]>>[F:40][C:41]1[CH:42]=[C:43]([C@@H:48]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58](=[O:59])[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])[CH3:49])[CH:44]=[CH:45][C:46]=1[F:47]
Reactant: C[C@@H](c1ccc(F)c(F)c1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)c(F)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(F)c(F)c1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(3,4-difluoro-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(3,4-difluoro-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound, too. Yield: 68% of theory; LC (method 6): tR=1.14 min; Mass spectrum (ESI+): m/z=324 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[Cl:22][C:23]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:30][C:24]1[CH:25]=[CH:26][C:27]([Br:29])=[CH:28][C:23]=1[Cl:22])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(Br)cc3Cl)cc2OC1C(F)(F)F
Temperature: 110 °C
Yield: 76.2 %

Procedure:
To the mixture of 1.5 g (4.61 mmol) of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 1.04 g (6.44mmol) of 2-chloro-4-bromophenol, and 0.89 g (8.76 mmol) potassium carbonate was added 10 mL of anhydrous DMF. The resulting mixture was heated to 110° C. for five hrs. After cooling to room temperature the reaction was treated with 150 mL of ethyl acetate. The organic phase was washed with saturated sodium bicarbonate three times and brine three times and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on a silica gel column with EtOAc/hexane (1:9) to afford 1.8 g (76.3%) of a light yellow solid: 1H NMR (CDCl3/400MHz) 7.69(s, 1H), 7.68(s, 1H), 7.47 (dd,1H, J=2.4 Hz, 8.7 Hz), 7.37 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.38(s, 1H), 5.70(q, 1H, J=6.6 Hz), 4.35 (m, 2H), 1.38(t, 3H, J=7.2 Hz). MS (ESI+) 511 (M+1, 60), 513 (M+3, 100); HRMS (El) m/z calcd for (C19H12BrCl2F3O4) 509.9248, found 509.9274.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:27])=[C:20]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:21]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:27])=[C:20]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)[CH:21]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: Fc1ccc(Br)cc1-n1ccnc1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-n4ccnc4)c3)cnc2c1F
Yield: 24 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 1-(5-bromo-2-fluorophenyl)-1H-imidazole as described in Example 6 to give 2-{8-fluoro-3-[4-fluoro-(3-imidazol-1-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as a pale yellow solid (83 mg, 24%): m/z (ES+) 355 [MH+].
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1>>[Br:6][C:7]1[CH:8]=[C:9]([S:13]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Yield: 106.4 %

Procedure:
Prepared by general procedure III from tert-butylamine (3.16 mL, 30 mmol) and commercially available 3-bromobenzenesulfonyl chloride (1.44 mL, 10 mmol) to give the title compound as a light yellow solid (3.11 g, 106%). MS (ISN) 290.1 [(M−H)−], 292.2 [(M+2−H)−].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][C:15]([O:17]CC)=[O:16].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:7]2.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: CCOC(=O)CBr
Agent: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cn1ccc2cc(Cl)ccc21
Reaction time: 0.5 h

Procedure:
To a suspension of NaH 60% dispersion in oil (1.52 g, 38 mmol) in DMF (50 mL) at r.t. there was added, in portions, 5-chloroindole (5.0 g, 33 mol) and the mixture was stirred for 30 minutes. There was added ethyl bromoacetate (7.44 g, 44 mmol) and the mixture was stirred for a further 5 hours. H2O (200 mL) was added and the mixture was extracted with Et2O. These extracts were washed with H2O, dried over MgSO4 and evaporated to a crude oily residue. Chromatography on silica gel, eluting with 5% EtOAc in toluene, afforded the ethyl ester of the title compound contaminated with some 5-chloroindole. This mixture was dissolved in EtOH (100 mL) and 2.5N aqueous NaOH was added (50 mL). The mixture was stirred at r.t. for 2 hours, then concentrated to a small volume. This residue was partitioned between H2O and Et2O, and by acidification of the aqueous fraction with 6N aqueous HCl, the title compound precipitated. The precipitate was filtered, washed with H2O and air-dried to afford the pure title product as a cream-colored solid.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Br:23])=[CH:13][N:12]=1)=[O:10])([C:6]#[N:7])[CH:3]1[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:32][OH:33]>C(O)C>[CH:3]1([C:2]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[C:14]([Br:23])=[CH:13][N:12]=2)=[O:10])([C:6](=[NH:7])[NH:32][OH:33])[CH3:1])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CC(C#N)(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)C1CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)(C(=N)NO)C1CC1
Temperature: 65 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (methyl-cyano-cyclopropyl-methyl)-amide (Example 78e, 900 mg, 2.29 mmol) in ethanol (15 ml) were added triethylamine (244 mg, 336 μl, 2.41 mmol) and hydroxylamine hydrochloride (167 mg, 2.41 mmol). The reaction mixture was then stirred at 65° C. for 18 hours. Volatiles were removed in vacuo and the residue was dissolved in ethylacetate which was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (576 mg, 59%) as a white solid. MS (ESI, m/z): 425.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([F:13])=[CH:6][C:3]=1[C:4]#[N:5].[OH2:14]>ClCCl>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([F:13])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: N#Cc1cc(F)cc([N+](=O)[O-])c1N
Reactant: O
Solvent: ClCCl
Product: NC(=O)c1cc(F)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of EXAMPLE 45B (13.9 g) in polyphosphoric acid (400 g) was stirred at 115° C. for 3 hours. After cooling, water and dichloromethane were added and the mixture stirred at ambient temperature for 10 minutes. The solid material was collected by filtration and recrystallized from methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].[CH2:15]([O:17]C=O)C.[H-].[Na+].C(OCC)(=O)C>COCCOC>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH:15]=[O:17])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccc(C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C=O)Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 16.0 g (0.083 mole) of 3-(6-methyl-3-pyridyl)-propionic acid ethyl ester and 9.6 g (0.13 mole) of formic acid ethyl ester is slowly added dropwise while cooling with ice to a suspension of 5.2 g of sodium hydride (80% on paraffin oil; 0.17 mole) in 30 ml of ethylene glycol dimethyl ether. On completion of the addition, the solution is stirred for 8 hours at room temperature. After the addition of 10 ml of ethyl acetate and 200 ml of ice water, the mixture is extracted three times with diethyl ether. The aqueous phase is diluted to pH 5.4 with dilute hydrochloric acid and the crystals precipitating are filtered under suction. Light brown crystals melting at 141°-142° C. are obtained in a yield of 12.8 g (70%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[F:51][C:52]1[CH:57]=[CH:56][C:55]([N:58]([CH3:60])[NH2:59])=[CH:54][CH:53]=1>CN(C=O)C.O1CCCC1>[F:51][C:52]1[CH:57]=[CH:56][C:55]([N:58]([CH3:60])[NH:59][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=2)=[CH:54][CH:53]=1
Reactant: CN(N)c1ccc(F)cc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 10 mL two-necked flask, the above synthesized 5-cyclopropyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (50 mg, 191 μmol, Eq: 1.00) was combined with tetrahydrofuran (1.00 ml) and DMF (1 ml) to give a colorless solution. TBTU (92.2 mg, 287 μmol, Eq: 1.5) and N,N-diisopropylethylamine (124 mg, 167 μl, 957 μmol, Eq: 5) were added and the reaction mixture was stirred for 10 min at rt; then 1-(4-fluorophenyl)-1-methylhydrazine hydrochloride (40.6 mg, 230 μmol, Eq: 1.2; CAN 1978-54-7) was added and the reaction allowed to proceed over night at rt. The reaction mixture was then quenched with 1 M HCl (10 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with 1 M NaOH, then with H2O/NaCl solution. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) delivered finally 70 mg of the title product as white semisolid; MS (EI) 384.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH:13][C:14](=O)[CH2:15][Cl:16])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:14]([CH2:15][Cl:16])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: O=C(CCl)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CC(=O)O
Product: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A stirred mixture of chloroacetic acid, 2-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl) hydrazide (23.7 g.) in acetic acid (280 ml.), under nitrogen was placed in an oil bath that had been preheated to 140° C. After 20 minutes the mixture was cooled and concentrated in vacuo. The residue was mixed with water, neutralized with sodium bicarbonate and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. Crystallization of the residue from ethyl acetate gave 18.1 g. of 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[3,4-a][1,4]benzodiazepine of melting point 187°-189° C. (dec.) and 1.74 g. of melting point 187°-189° C. (dec.). This product was the same as that obtained in Preparation 2.
Reaction SMILES: [CH2:1](Br)[CH3:2].[C:4]1([CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:10][C:1]=1[CH3:2])[CH3:9]
Reactant: CCBr
Reactant: Cc1ccccc1
Product: CCc1ccccc1C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a mixture of 3.8 g of the complex obtained in Example 1 and 97.3 g of toluene were added dropwise 83 g of ethylbromide at 20° to 25°C over 1 hour and a half while stirring. The reaction solution was held at 50° to 60°C for 1 hour after a dropwise addition, washed with water then alkali and rectified to obtain 64.2 g of ethyltoluene distillate. The resulting distillate was a mixture consisting of m- and p-isomers as main ingredients and a msall amount of o-isomer.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1NC1CCCC1

Procedure:
4-Chloro-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.89 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (200 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (140 mg) following general procedure E. The above ethylamide (0.42 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-cyclopentyl-3-ethyl-9-fluoro-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (13 mg). LCMS: m/z 358 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H][H]>CO.[Pd].C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N2CCNCC2)cc1

Procedure:
4-(4-Benzyl-piperazin-1-yl)-benzoic acid methyl ester (19.4 mmol) is dissolved in methanol (150 ml) and Pd/charcoal is added (0.6 g). The mixture is stirred in a hydrogen atmosphere until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A powder with mp. 95-97° C. is obtained.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:18]([N:20]([CH2:23][CH2:24][Cl:25])[CH2:21][CH3:22])[CH3:19]>>[ClH:25].[CH2:18]([N:20]([CH2:23][CH3:24])[CH:21]([C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:8][NH:9]2)[CH3:22])[CH3:19]
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)C(C)c1c(C)ccc2[nH]nc(-c3ccccc3)c12
Yield: 58.1 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-methylindazole (4.17 g) and diethylaminoethyl chloride hydrochloride (5.16 g) were treated to obtain 4.0 g of 1-diethylaminoethyl-3-phenyl-5-methylindazole hydrochloride (m.p. 131°-133° C).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([C:27]2[CH:32]=[N:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=2)=[O:5])=[CH:7]1
Reactant: COc1ncc(I)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ncc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 119 mg (0.33 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 183 mg (0.73 mmol) of 5-iodo-2-methoxy-3-methyl-pyridine in 1 mL THF with 0.38 mL 2M isopropylmagnesium chloride. Yield: 86 mg of a white powder. LC-MSD, m/z for C24H19ClN2O3 [M+H]+=419.1, 421.1; HPLC retention time: 3.1 min.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:3](=O)[CH3:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:28][C:29]([NH2:31])=[S:30])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:2]2[S:30][C:29]([NH:28][C:18]3[CH:19]=[CH:20][C:21]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:31][C:3]=2[CH3:4])=[CH:8][CH:9]=1
Reactant: CC(=O)C(Cl)Cc1ccc(Cl)cc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)c(Cc3ccc(Cl)cc3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 72 mg (0.33 mmol) 3-chloro-4-(4-chlorophenyl)-2-butanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 78 mg (61%) [5-(4-chloro-benzyl)-4-methyl-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light brown solid. MS ISP (m/e): 425.1/427.1 (100/42) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.15 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.37 (d, 2H), 7.26 (d, 2H), 7.23 (s, 2H), 3.98 (s, 2H), 3.77 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1[CH3:17].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[NH4+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C:9]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=1/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc([N+](=O)[O-])c1C
Temperature: 125 °C
Reaction time: 36 h

Procedure:
Under argon, 119.5 g (1.39 mol) of methyl acrylate were added dropwise to a mixture of 100 g (0.463 mol) of 2-bromo-6-nitrotoluene, 323 ml (2.31 mol) of triethylamine, 28.2 g (92.6 mmol) of tri-2-tolylphosphine and 10.4 g (46.3 mmol) of palladium(II) acetate in 2.0 liters of DMF, and the mixture was then stirred at 125° C. for 36 h. After cooling to room temperature, the reaction mixture was stirred with 4 liters of saturated aqueous ammonium chloride solution and extracted three times with a total of 5 liters of diethyl ether. The combined organic phases were washed with water and saturated sodium chloride solution and dried over sodium sulphate. After filtration, the solvent was removed to dryness under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 6:1). The product was triturated with heptane, and the solid obtained was filtered off with suction and dried under high vacuum. This gave 48.7 g of the title compound (46.6% of theory).
Reaction SMILES: [C:1]1([C:12]2[C:13]([NH2:22])=[CH:14][CH:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)[C:2]([NH2:11])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([NH:22][C:13]2[C:12]([C:1]3[C:2]([NH:11][S:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=4)(=[O:31])=[O:30])=[CH:3][CH:4]=[C:5]4[C:10]=3[CH:9]=[CH:8][CH:7]=[CH:6]4)=[C:21]3[C:16](=[CH:15][CH:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Nc1ccc2ccccc2c1-c1c(N)ccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3ccccc3c2-c2c(NS(=O)(=O)c3ccc(C)cc3)ccc3ccccc23)cc1
Yield: 95 %

Procedure:
Under nitrogen atmosphere, to a solution in which 1,1′-binaphthyl-2,2′-diamine (0.5 mmol) was dissolved in pyridine (1 mL) was added p-toluenesulfonyl chloride (1.1 mmol) at room temperature, and the mixture was reacted for 5 to 12 hours with stirring. After completion of the reaction, the resulting red suspension was diluted with ethyl acetate, and back-extracted with 1N hydrochloric acid to remove pyridine. The resulting organic layer was dried with sodium sulfate to remove the solvent, and the residue was purified by column chromatography to obtain an objective substance as a pale yellow to white solid in more than 95% yield.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH2:25](I)[CH3:26]>C1COCC1>[CH2:25]([C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1)[CH3:26]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: CCI
Solvent: C1CCOC1
Product: CCc1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butylithium at −78° C. After stirring at −78° C. for 10 min, ethyl iodide was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.89(s, 2H), 6.07(s, 1H), 3.72(d, 1H), 3.34(m, 1H), 2.58(q, 2H), 2.16(s, 3H), 2.12(s, 3H), 2.09(s, 6H), 1.4-1.7(m, 4H), 1.25(t, 3H), 0.96(t, 6H) ppm.
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1>>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH2:2][CH:3]=[O:4])=[CH:7][CH:6]=1
Reactant: O=CCCl
Reactant: SCc1ccncc1
Product: O=CCSCc1ccncc1

Procedure:
By the method of the preceding Example, chloroacetaldehyde is reacted with 4-picolyl mercaptan to yield title product.