Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:3]=1.[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:21][C:22]1[S:26][C:25]([S:27]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[F:11])[N:4]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[N:3]=2)(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: N#Cc1cccc(Cn2nc(N)c3c(F)cccc32)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: N#Cc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(F)cccc32)c1
Temperature: 0 °C

Procedure:
To a solution of 3-[(3-amino-4-fluoro-1H-indazol-1-yl)methyl]benzonitrile (for a preparation see Intermediate 37) (695 mg, 2.61 mmol) in anhydrous pyridine (3 mL) cooled in an ice/water bath was added 5-chloro-2-thiophenesulfonyl chloride (567 mg, 2.61 mmol) dropwise over 1 minute and the reaction mixture was stirred in the ice/water bath for 1 hour. The reaction mixture was partitioned between ethyl acetate (150 mL) and 2N hydrochloric acid (100 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a dark red oil (1.264 g). The oil was dissolved in the minimum volume of dichloromethane, applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-50% ethyl acetate in cyclohexane gradient over 60 min. Fractions 66-69 were combined and evaporated in-vacuo to yield a white foam (540 mg), which was further purified by chromatography on 100 g silica SPE cartridge on Flashmaster II using a 0-10% methanol in dichloromethane gradient over 60 min. Fractions 23-26 were evaporated in-vacuo to yield the title compound as a white foam (493 mg, 42%). LCMS (SystemB) RT=3.01 min, ES+ve m/z 447/449 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:13]=[C:14]([C:18]2[N:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[Cl:3][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:27])([F:26])[F:10])[CH:13]=2)=[N:23][CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2cccc(C(F)(F)F)c2)nc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
911 mg (0.56 ml, 7.66 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 970 mg (3.83 mmol) [6-(3-Trifluoromethyl-phenyl)-pyridine-3-yl]-methanol in 30 ml dichloromethane, stirred for 5 min. at 0° C., and at r.t. for 1 h. The mixture is poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), and evaporated. Purification by chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 750 mg (72%) of 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine as light yellow crystals
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:1].[ClH:1].[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:13][CH2:14]2)[CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: O=C(O)CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1
Agent: Cl
Product: O=C(CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1)OC1CCCCC1

Procedure:
Prepared from 4-[[4-(4-piperidinyl)-piperazin-1-yl]carbonylamino]piperidinoacetic acid dihydrochloride and cyclohexanol.
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:30]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:27])[CH:9]([Br:30])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1Br
Yield: 52.9 %

Procedure:
The carboxylic acid (22.4 g) prepared by hydrolyzing 29.6 g of ethyl 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-4-heptenoate with 80 ml of 4N sodium hydroxide solution in 500 ml of methanol, was treated with 9.73 g of bromine in an aqueous sodium hydrogen carbonate solution and the reaction mixture was worked up according to the method described in Example 1 (b). The product was recrystallized from a mixture of n-hexane and acetone (10:1) to yield 13.5 g of the desired compound melting at 155°-160° C.
Reaction SMILES: NC1C=CC(C([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15]C)[CH2:11][CH2:10]2)=O)=CC=1Cl.[NH2:20][C:21]1[C:29]([O:30][CH3:31])=[CH:28][C:24]([C:25]([OH:27])=O)=[C:23]([Cl:32])[CH:22]=1.CN1CCC(N)CC1>>[NH2:20][C:21]1[C:29]([O:30][CH3:31])=[CH:28][C:24]([C:25]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[O:27])=[C:23]([Cl:32])[CH:22]=1
Reactant: COc1cc(C(=O)O)c(Cl)cc1N
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Agent: CN1CCC(N)CC1
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(Cl)cc1N

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 3.06 mmol scale utilising 4-amino-2-chloro-5-methoxy-benzoic acid (Intermediate 217; 617 mg, 3.06 mmol) and 1-methylpiperidin-4-amine (Fluorochem; 385 mg, 3.37 mmol), as an off-white solid (845 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:26]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
67 mg (0.24 mmol) of 3-fluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 40 mg (0.24 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 4 ml of water/ethanol 1:1. 25 μl (0.29 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7 and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=2)[C:10]1=[O:19].[CH2:20]([O:22]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:21]>>[C:20]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=2)[C:10]1=[O:19])(=[O:22])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1c2ccc(Cl)cc2CC1Cc1ccncc1Br
Product: CC(=O)c1cnccc1CC1Cc2cc(Cl)ccc2C1=O

Procedure:
The title compound 110 is prepared according to the procedure reported in Example 36.5 with compound 109 (317 mg, 0.94 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.31 mL, 0.94 mmol) as reactants. White solid. (Yield 221 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:13]2[C:14](O)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([N:25](CC)CC)C.ClC(OCC)=O.N>O1CCCC1>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:13]2[C:14]([NH2:25])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.83 h

Procedure:
3.10 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline and 1.10 g of triethylamine were dissolved in 40 ml of dried tetrahydrofuran, and a solution of 1.20 g of ethyl chloroformate in 10 ml of dried tetrahydrofuran was added dropwise thereto at -25° C. to -35° C. After stirring at the same temperature for 50 minutes, 10 ml of concentrated aqueous ammonia was added dropwise to the mixture at -25° to -40° C. The temperature was then gradually elevated to room temperature, and the reaction mixture was stirred for 1 hour, followed by concentration under reduced pressure. To the residue were added 20 ml of water and 50 ml of diethyl ether. After ice-cooling, the thus formed white crystals were separated by filtration, washed successively with cool water and cool diethyl ether, and dried under reduced pressure to yield trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:35]2[CH:40]=[CH:39][C:38](Br)=[CH:37][CH:36]=2)([CH:14]([O:23][C:24]2[NH:28][C:27]3[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:26]=3[N:25]=2)[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)#[N:43].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:35]2[CH:40]=[CH:39][C:38]([C:48]3[CH:47]=[CH:46][CH:45]=[C:44]([C:42]#[N:43])[CH:49]=3)=[CH:37][CH:36]=2)([CH:14]([O:23][C:24]2[NH:28][C:27]3[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:26]=3[N:25]=2)[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)(C(COCC[Si](C)(C)C)Oc2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cccc(C#N)c3)cc2)(C(COCC[Si](C)(C)C)Oc2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A mixture of 0.105 g of 4-(4-bromo-phenyl)-4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester 51 (0.144 mmol, 1 eq), 0.024 g of 3-cyanophenyl boronic acid (0.16 mmol, 1.1 eq), and 0.034 g of Pd(PPh3)4 (0.03 mmol, 20 mol %) was mixed with 3 mL of toluene, 2 mL of ethanol and 1 mL of 2M aqueous Na2CO3 and then heated at 80° C. for 20 h while stirring. The reaction was allowed to cool to room temperature, diluted with 25 mL of ethyl acetate and washed with 25 mL of saturated brine. The organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product which was purified by flash column chromatography eluting with a gradient of 5-20% ethyl acetate in hexane to give 0.081 g of 4-(3′-cyano-biphenyl-4-yl)-4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester 52 as a pale foam: 1H NMR (300 MHz, CDCl3): δ 7.82-7.76 (m, 2H), 7.59-7.48 (m, 7H), 7.13-7.10 (m, 1H), 5.17 (s, 2H), 4.53 (s, 2H), 3.85-3.80 (br. d, 2H), 3.41-3.36 (t, 2H), 3.18-3.10 (t, 2H), 2.36-2.3 (d, 2H), 2.00-1.96 (t, 2H), 1.44 (s, 9H), 0.83-0.77 (t, 2H), 0.10 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: CN
Reactant: O=C(O)c1ccc(CBr)cc1
Product: CNCc1ccc(C(=O)O)cc1

Procedure:
4-Bromomethyl-benzoic acid (5 g, 22.8 mmol) is treated with a methylamine solution (40%, 75 mL, 867 mmol) for 4 days at ambient temperature. The resulting mixture is evaporated and the residue purified by flash chromatography.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[CH:10][C:11]([O:13]C)=[O:12])[CH2:3]2>Cl>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[CH:10][C:11]([OH:13])=[O:12])[CH2:3]2
Reactant: COC(=O)C=C1CN2CCC1CC2
Agent: Cl
Product: O=C(O)C=C1CN2CCC1CC2
Reaction time: 72 h

Procedure:
Methyl quinuclidin-3-ylideneacetate hydrochloride (1 g) was heated in concentrated hydrochloric acid (10 ml) at 60° C. for 18 hrs and the solution evaporated to dryness. The residue was kept under vacuum over P2O5 for 3 days to give quinuclidin-3-ylidene acetic acid hydrochloride, 0.91 g (97%) as a white solid; 1H NMR (D2O) inter alia 5.77 (broad s) and 5.86 (broad s) (ca. 1:1, vinyl protons of the two geom. isomers).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]3)[CH2:28][CH2:29]2)[CH:21]=[C:20]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCn3ncc(=O)[nH]c3=O)CC2)n1

Procedure:
2-{4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4]triazine-3,5-dione was prepared from 2-(4-chloro-butyl)-2H-[1,2,4]triazine-3,5-dione and 2-tert-butyl-4-piperazin-1-yl-6-cyclobutylpyrimidine by analogy to the process described in example 1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=O.O.O.[NH2:15][NH2:16]>>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:15][NH:16]2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: O
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 2-fluoro-4-methoxyactophenone (2.0 g, 12 mmol) in hydrazine hydrate (30 mL) was heated at reflux for two days. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (3×). The organic extracts were concentrated, dissolved in a minimal amount of CH2Cl2 and filtered to afford 6-methoxy-3-methyl-1H-indazole (370 mg, 19%). The filtrate was refiltered to provide additional product (250 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2cc(-c3ccc(Cl)cc3)on2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cc(-c3ccc(Cl)cc3)on2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of methyl 3-[5-(4-chlorophenyl)-3-isoxazolyl]benzoate (1.10 g), 1 M aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (15 ml) and methanol (15 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (5 ml) was added. The crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give 3-[5-(4-chlorophenyl)-3-isoxazolyl]benzoic acid (0.91 g, yield 87%) as colorless crystals. melting point: 298–299° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15].[CH3:22]I.Cl>CCCCCC.CS(C)=O>[OH:3][C:4]1[C:13]([O:14][CH3:22])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15]
Reactant: CI
Reactant: O=C1CC(c2ccccc2)Cc2c1ccc(O)c2O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc2c(c1O)CC(c1ccccc1)CC2=O
Yield: 43 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.39 g, 9.8 mmol) was washed with hexane and the hexane was decanted. DMSO (15 mL) was added to the sodium hydride and the resultant suspension was stirred vigorously. To the suspension was added a solution of 2.5 g (9.8 mmol) of 5,6-dihydroxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, from Step 1, in 10 mL of DMSO. The mixture was stirred at ambient temperature for 80 min and 0.61 mL (9.8 mmol) of methyl iodide was added in one portion. The reaction mixture was stirred at ambient temperature overnight and then made acidic with 5% aqueous hydrochloric acid solution. The mixture was stirred for 30 min and then filtered. The filter cake was dissolved in 20% ethyl acetate in hexane and chromatographed on a silica gel column eluted with 20% ethyl acetate in hexane and 50% ethyl acetate in hexane to give a brown solid. The solid was crystallized from ethyl acetate to give 1.13 g (43% yield) of the title compound as white crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.[CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>>[CH:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:6]=3[N:7]=2)[CH2:32][CH2:31]1)=[O:29]
Reactant: O=CN1CCNCC1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCCc4ccccc4)ncnc23)CC1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(NCCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 181 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenethylamino-pyrimido-[5,4-d]-pyrimidine (m.p.: 198°-200° C.) and N-formyl-piperazine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].O1CCCC1>O>[C:26]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:28])[CH3:27]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O

Procedure:
A mixture of 25.0 g. (0.075 mole) of 1-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole and 225 g. (2.25 mole) of acetic anhydride was heated under reflux for 3 hours, diluted with 200 ml. of tetrahydrofuran, and poured into 3 l. of water. An oil separated and slowly solidified. Recrystallization from acetic acid gave a tan solid, m.p. 155°-162°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23](OC)=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH3:27].CO>>[Br:1][C:2]1[CH:3]=[C:4]([C:23]([NH2:27])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 105 °C
Yield: 75.8 %

Procedure:
Methyl 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.008 g, 2.410 mmol, Example 212D) was suspended in NH3/MeOH (7M) (18 mL, 126 mmol) in a sealed microwave vial. The mixture was heated at 105° C. for 8 hours in a microwave reactor. Product crystallized from reaction mixture upon cooling and was collected by filtration, washed with MeOH and dried in nitrogen stream to give 736.4 mg 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamide. 1H NMR (DMSO-d6) δ ppm 11.4 (b, 1H), 8.56 (s, 1H), 8.22 (d, 1H, J=8.6), 7.81 (s, 1H), 7.31 (dd, 1H, J=7.9, 1.2), 3.75-3.35 (b, 10H). MS (ESI) m/e−=401/403, m/e+=403/405 (1 Br isotope pattern) consistent with [M−H]− and [M+H]+. HPLC retention time 6.74 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[Cl:10][C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>C(#N)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([N:6]2[CH2:7][CH2:8][NH:9][C:5]2=[N:4][N+:1]([O-:3])=[O:2])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])N=C1NCCN1
Solvent: CC#N
Product: O=C(Nc1cccc(Cl)c1)N1CCNC1=N[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 3.9 g of 2-nitroiminoimidazolidine and 4.6 g of 3-chlorophenylisocyanate in 80 ml of dry acetonitrile was refluxed for 3 hours. After cooling to room temperature, the precipitated crystals were filtered, and washed with ether to give desired 1-(3-chlorophenylcarbamoyl)-2-nitroiminoimidazolidine. The yield was 4.7 g.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([NH2:19])[C:16]([C:20]#[N:21])=[C:15](Cl)[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[NH2:19][C:17]1[C:16]([C:20]#[N:21])=[C:15]([NH:30][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[N:14]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:23]=[CH:24][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:12])[CH:18]=1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)c1ccc(CNC(=O)c2cc(N)c(C#N)c(Cl)n2)cc1
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cc(N)c(C#N)c(NC3CCCC3)n2)cc1
Temperature: 160 °C
Yield: 81 %

Procedure:
A mixture of Example 181F (36.5 mg, 0.1 mmol) and cyclopentylamine (25.5 mg, 0.3 mmol) in N,N-dimethylacetamide (1.5 ml) was stirred in a sealed tube. This reaction mixture was heated in a microwave reactor at 160° C. for 20 min. and purified on HPLC (10 mM ammonium acetate, 5% acetonitirle in H2O/CH3CN) to give titled compound (33.5 mg, 81%). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (t, J=6.0 Hz, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 6.89 (s, 2H), and 6.70 (s, 1H), 6.27 (d, J=6.0 Hz, 2H), 4.57 (d, J=6.0 Hz, 2H), 4.57 (m, 1H), 3.18 (s, 3H), 1.95 (m, 1H), 1.67 (m, 2H), 1.50 (m, 4H); MS (APCI) m/z 414 [M+H]+, 412 [M−H]−.