Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][CH:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:37][S:34]([CH:32]([CH3:33])[CH3:31])(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CC(C)S(N)(=O)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) and propane-2-sulfonamide as described in Example 181, Step A. MS (ESI) m/z=551 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1([Cl:16])[CH2:13][CH:12]1[CH2:14][NH2:15].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([NH:15][CH2:14][CH:12]2[CH2:13][C:11]2([Cl:16])[Cl:10])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCC1CC1(Cl)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCC2CC2(Cl)Cl)n1

Procedure:
A mixture consisting of 38.8 gm (0.24 mol) of 2-amino-4,6-dichloro-pyrimidine, 300 ml of ethanol, 33.1 gm (0.24 mol) of (2,2-dichloro-cyclopropylmethyl)amine and 36 ml (0.26 mol) of triethylamine was refluxed for six hours while stirring. Thereafter, the solvent was distilled off, the oily residue was stirred with about 300 ml of acetone, and the precipitated triethylamine hydrochloride was suction-filtered off. The acetone was distilled out of the filtrate in vacuo, and the residue was admixed with 500 ml of diisopropyl ether and 100 ml of water. The organic phase was separated and again washed with water, dried with magnesium sulfate, de-colorized and evaporated. The residue was triturated with gasoline (b.p. 40°-60° C.) to yield the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][S:17][CH2:18][CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>>[CH3:16][S:17][CH2:18][CH2:19][CH2:20][NH:21][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CSCCCN
Solvent: CCN(CC)CC
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 83.8 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6- dichloro-3-nitrobenzenesulfonyl chloride (2 g, 6.88 mmol), 3-(methylthio)propylamine (0.72 g, 6.88 mmol) and triethylamine (1.92 mL, 13.76 mmol) were reacted to form the desired product (2.07 g, 82%). 1H NMR (MeOD-d4): δ 7.93 (d, 1H), 7.79 (d, 1H), 3.16 (t, 2H), 2.47 (t, 2H), 2.00 (s, 3H), 1.76 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].[N:22](OCCC(C)C)=[O:23]>C1COCC1.CCOC(C)=O>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=[N:22][OH:23])[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:19])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)CCON=O
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1nc(C(=NO)C(=O)c2ccccc2)ccc1=O
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (513 mg) was added to a suspension of NaH (60% dispersion in mineral oil) (84 mg) in THF (5 ml) and the mixture was stirred at 45-50° C. for 30 minutes. After addition of isoamyl nitrite (0.27 ml), the mixture was stirred at the same temperature for 8 hours. The mixture was dissolved in EtOAc, washed with 1N HCl and brine and dried over MgSO4. The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime as a solid (185 mg).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6]([NH:13][C:14](=[O:25])[CH2:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH2:15][C:14]([NH:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:25])=[S:4]
Reactant: O=C(CCC(=O)c1ccccc1)NCc1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCC(=O)NCc1ccccc1)c1ccccc1
Yield: 87.9 %

Procedure:
Thiosemicarbazide (2.30 g, 25.2 mmol) was added to a solution of N-benzyl-4-oxo-4-phenyl-butyramide (4.12 g, 15.4 mmol), prepared in the previous step, in 100 ml of methanol plus 4.2 ml of 1 N HCl plus 4.2 ml of water and the reaction stirred at room temperature for 20 hours. The reaction was cooled in an ice bath and a white solid precipitated. The solid was collected by filtration and dried to give 4.61 g of a white solid. Recrystallization of the solid from ethyl acetate-methanol gave the title compound (2.05 g, 39%) as a white solid, mp 162-164° C.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)CN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CC(C)C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 38.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-isobutyl-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.0 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: Cc1noc(-c2sc(NC(=O)c3ccco3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and furan-2-carbonyl chloride.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)[OH:12])=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:10][CH:9]([C:1]1[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=1)[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[CH:19][CH:20]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(C(=O)C(OC2CCCCO2)c2ccc(OC)cc2)cc1
Yield: 71.6 %

Procedure:
82 parts of p-anisoin are reacted with 34 parts of 3,4-dihydro-2H-pyran (approx. 35% molar excess) in 500 parts by volume of benzene, analogeously to Example 1. p-anisoin tetrahydropyranyl ether is obtained in a yield of 71.6% and melts over the range of 96° to 102° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:31]I>O1CCCC1>[CH:1]1([N:7]([CH3:31])[C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCCC3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of methyl 3-(cyclohexylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.53 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (105.5 mg, 4.40 mmol) and CH3I (299.9 mg, 2.11 mmol), and the reaction was allowed to proceed with stirring overnight at room temperature. The reaction was then quenched by the addition of water (50 mL), adjusted pH to 5 with HCl (3N). The resulting solution was extracted with ethyl acetate (3×80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the crude product. The crude product was re-crystallized from ethyl acetate:petroleum ether (1:5) to afford 3-(cyclohexyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (100 mg, 48%) as a light yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([O:30]C)=[O:29])[C:19]([CH3:35])=[C:18]4[CH3:36])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([OH:30])=[O:29])[C:19]([CH3:35])=[C:18]4[CH3:36])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C5CC5)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1c(C)n(Cc2cccc(C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12

Procedure:
A solution of (S)-Methyl 3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)benzoate (˜0.07 mmol) and NaOH (2 M, 0.5 mL) in MeOH (2 mL) and DMSO (1 mL) was stirred at rt for 15 h. It was neutralized and purified by preparative HPLC to yield the title compound as a white solid. ESI-MS (m/z): 467 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[C:3]1=[O:21].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23].C(Cl)Cl>>[OH:28][C:22]([C:24]([F:27])([F:26])[F:25])=[O:23].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[C:3]1=[O:21]
Reactant: Cc1cccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(N2CC(C(=O)O)N(C)C2=O)n1

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (300 mg, 1.5 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-6-methylpyridine (258 mg, 1.5 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (733 mg, 2.25 mmol), Xantphos™ (65.1 mg, 0.113 mmol) and tris(dibenzylideneacetone)dipalladium(0) (34.3 mg, 0.038 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (246 mg, 56%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (246 mg, 0.84 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was dried to give 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.84 mmol) which was used in the next step. LC/MS [M+H]+=236.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O)=[CH:13][C:12]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:11]([O:34][CH3:35])[CH:10]=2.O.O.[Sn](Cl)Cl>O.Cl>[CH2:27]([O:26][C:12]1[C:11]([O:34][CH3:35])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:5][N:1]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=4)[C:15]=3[C:14]=2[CH:13]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=N[O-]
Reactant: COc1cc2ncc(N)c(C(=O)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2ncc3[nH]nc(-c4ccc(C#N)cc4)c3c2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of sodium nitrite (483 mg, 6.99 mmol) in water (2.5 ml) is added dropwise over the course of 1.5 h at (−)1-0° C. to a suspension of 4-(3-amino-6-benzyloxy-7-methoxy-quinoline-4-carbonyl)benzonitrile (2.60 g, 6.35 mmol) in concentrated hydrochloric acid (50 ml). The mixture is subsequently stirred for a further 30 min. A solution of tin(II) chloride dihydrate (5.02 g, 22.23 mmol) in concentrated hydrochloric acid (3.8 ml) is then added at (−)5° C. The suspension obtained is stirred at room temperature for 1 h, subsequently diluted with water (500 ml), stirred for 30 min and filtered with suction. The filter cake is rinsed with water and dried in a high vacuum, giving 4-(8-benzyloxy-7-methoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (2.42 g, 5.95 mmol) as a solid having a melting point of 222.8° C. (decomposition). MS: 407.1 (M+H+), TLC (HPTLC): Rf=0.27 (ethyl acetate).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:12][CH2:11]1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]2[C:17](=[O:26])[C:18]3=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]3[C:20]2=[O:21])[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (60 g; 0.39 mol) was added in portions to a mixture of trans N-(4-hydroxycyclohexyl)phthalimide (D62, 95 g; 0.39 mol), imidazole (55 g; 0.78 mol), and DMF (200 mL) at 20-30° C. (internal, ice cooling). After stirring for 3 h more at 40° C. the mixture was partitioned between water/hexane. Drying and evaporation of the organic layer gave the title compound (92 g) crystallised from pentane.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36]
Reactant: COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid methyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with methyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.94-2.06 (m, 4H), 3.09-3.14 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.61 (s, 3H), 4.02-4.10 (m, 2H), 4.98-5.04 (m, 1H), 7.59-7.61 (m, 2H), 8.02-8.04 (m, 2H), 8.35 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=432.
Reaction SMILES: [OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC2(O)CCNCC2)cc1
Yield: 100 %

Procedure:
A mixture of 23 parts of ethyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzoate and 200 parts of ethanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 17 parts (100%) of ethyl 4-[(4-hydroxy-4-piperidinyl)methoxy]benzoate as a residue (int. 79).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([NH:35][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CC(C)(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)(C)C)O2
Yield: 20.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 355 mg CDI (2.20 mmol) and 160 mg t-butylamine (2.20 mmol) produced 125.1 mg of N-tert-butyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: C1(=O)[N:5]([CH:6]([C:9]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][NH:13]3)[CH2:7][CH3:8])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]([C:9]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][NH:13]2)[CH2:7][CH3:8]
Reactant: CCC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCC(N)c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
1-Phthalimidopropyl-3-phenyl-5-chloroindazole (8.3 g) and hydrazine hydrate (2.0 g) were added to ethanol (150 ml) followed by heating under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and to the residue were added benzene (150 ml) and 10% aqueous sodium hydroxide solution (200 ml) followed by stirring at room temperature for 1 hour. The organic layer was separated from the mixture and it was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 5.5 g of 1-aminopropyl-3-phenyl-5-chloroindazole as an oily product. The product was treated with ether-hydrochloric acid to form its hydrochloride. After recrystallization from ethanol-ether, the product had a melting point between 163°-164° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2.[ClH:29].[CH3:30]COCC>>[ClH:29].[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[CH2:14][C:15]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CN(C)CCc1[nH]c2ccccc2c1CC1(c2ccccc2)CCCCC1=O
Reactant: CCOCC
Agent: Cl
Product: CN(C)CCc1c(CC2(c3ccccc3)CCCCC2=O)c2ccccc2n1C

Procedure:
The same procedure was used to methylate 37.5 g (0.1 mol) of 2({2-[2-(dimethylamino)ethyl]indol-3-yl}methyl)-2-phenylcyclohexanone. The residue obtained on evaporation of the ethereal extraction solvent was redissolved in ether and treated with ethereal hydrogen chloride. The crude hydrochloride salt was collected and recrystallized from 750 ml of isopropyl alcohol to give 25.8 g of product, mp 246°-247°dec.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)(C)C>[OH:8][C:9]1[CH:10]=[C:11]([C@H:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(O)c(O)c1
Yield: 84 %

Procedure:
A mixture of methyl (4S,5R)-5-(3,4-dibenzyloxyphenyl)-2-phenyl-2-oxazoline4-carboxylate (494 mg, 1.00 mmol), 5%-palladium-carbon (64 mg) and isopropanol (5 g) was reduced with hydrogen at room temperature under atmospheric pressure for 15 hours. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure. The residue was treated with silica gel chromatography to obtain 263 mg (0.84 mmol, yield: 84%) of methyl (4S,5R)-5-(3, 4-dihydroxyphenyl)-2-phenyl-2-oxazoline-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-phenylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=448.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:21]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:25]([CH:21]3[CH2:24][CH2:23][CH2:22]3)=[O:26])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCC2)CC1
Reaction time: 2 h
Yield: 22 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.063 g, 0.22 mmol, from Example 47, Step 1) was combined with cyclobutanecarboxylic acid chloride (0.037 mL, 0.32 mmol) and triethylamine (0.090 mL, 0.64 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and then concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (18 mg, 22%). LCMS calculated for C20H23ClN3O2 (M+H)+: m/z=372.1; Found: 372.1.