Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]([OH:16])[CH3:15])[N:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([CH:14]([OH:16])[CH3:15])[CH:13]=1
Reactant: CC(O)c1cc(NC(=O)OC(C)(C)C)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1cc(N)ncn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A solution of [6-(1-hydroxyethyl)-pyrimidin-4-yl)-bis-carbamic acid tert-butyl ester and [6-(1-hydroxyethyl)-pyrimidin-4-yl)-carbamic acid tert-butyl ester (200 mg+198 mg, 1.45 mmol) in DCM (6.0 mL) was cooled to 0° C. and TFA (6.0 mL) was added. The reaction mixture was stirred at 0° C. for 15 minutes, then at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution and 2-methyltetrahydrofuran (×2). The aqueous layer was then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% methanol in DCM) to afford the title compound as a colorless oil (195 mg, 96% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.54 (br s, 2H), 6.67 (s, 1H), 4.73-4.65 (m, 1H), 1.37 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:25]([N+:28]([O-])=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1>C(O)(=O)C.C(OC(=O)C)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Yield: 82.8 %

Procedure:
353 mg of iron dissolved in aqueous 5% acetic acid solution was activated at 100° C. 450 mg of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[7 (3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-amine (see, Journal of Medicinal Chemistry 2000, 43, 1380) dissolved in a mixture of ethylacetate and acetic acid (1:1) was added thereto dropwise, and refluxed. The hot reacted solution was filtered under a reduced pressure through celite pad, and the pad was washed with ethylacetate. The washed solvent was washed with saturated sodium bicarbonate solution several times. The organic layer was dried over magnesium sulfate, and filtered and distilled under a reduced pressure to obtain the title compound (353 mg, 83%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)[CH3:35])[CH2:30]C>>[CH2:29]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:42][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:40][CH:41]=1)[CH3:35])[CH3:30]
Reactant: CCCOC(=O)C(C)c1ccc(CBr)cc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOC(=O)C(C)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2-(4-Bromomethyl-phenyl)-propionic acid propyl ester as in the procedure of Example 43. MS m/z 570;
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH:10]2OCC[O:11]2)=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>CO.O.Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1
Reactant: Fc1ccccc1Cc1ccc(C2OCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(Cc2ccccc2F)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2-(5-(2-Fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 122 (4.33 g, 16.4 mmol) was dissolved in a mixture solvent of methanol (40 mL) and water (10 mL), 1N hydrochloric acid (20 mL) was added thereto, followed by stirring at room temperature for 1 hour. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (3.54 g, 16.1 mmol, 98%) was obtained as a light yellow oil.
Reaction SMILES: O1C2C=CC=CC=2N=C1.NC1C=CC=CC=1.C(OC([N:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[C:41]3[O:40]C(C(C)(C)C)=[N:38][C:37]=3[CH:36]=[CH:35][C:34]=2[Cl:46])(=[O:32])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C.OS(O)(=O)=O>O1CCOCC1.O>[NH2:38][C:37]1[C:41]([OH:40])=[C:33]([S:30]([N:27]2[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]2)(=[O:32])=[O:31])[C:34]([Cl:46])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Solvent: Nc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCNCC2)c1O
Yield: 97.2 %

Procedure:
Following the general procedure for the hydrolysis of the benzooxazole to the desired aniline outlined in example 51, 4(2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 4.3 mmol), water (3.65 mL), and H2SO4 (3.65 mL) in 1,4-dioxane (60 mL) were reacted to afford the title compound (1.22 g, 96%). LCMS m/z 292(M−H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)c1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-n-butylaminocarbonyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2OS(C(F)(F)F)(=O)=O.[CH:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[NH4+].[Cl-].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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:31]=1
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2[nH]c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)c1cccc(-c2c(C#N)c(=O)[nH]c3ccc(Cl)cc23)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of trifluoro-methanesulfonic acid 6-chloro-3-cyano-2-oxo-1,2-dihydro-quinolin-4-yl ester (400 mg, 1.13 mmol, Eq: 1.00), 3-isopropylphenylboronic acid (223 mg, 1.36 mmol, Eq: 1.2), potassium phosphate tribasic (361 mg, 1.7 mmol, Eq: 1.5) and tetrakis(triphenylphosphine)palladium (0) (65.5 mg, 56.7 μmol, Eq: 0.05) in dioxane (8.00 ml) was heated to 100° C. for 4 h. The reaction mixture was cooled to RT, diluted with sat. NH4Cl solution and extracted with ethyl acetate (2×). The combined extracts were washed with sat. NH4Cl solution and brine, dried with Na2SO4 and evaporated. Diethylether was added to the remaining red solid and the mixture was stirred for 2 h. Then the orange solid was filtered off (222 mg). MS (ESI): 323.2 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1.N1C=CC=CC=1.F.N1C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:10][C@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:12][C@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(NCC4CC4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCC4CC4)ncnc32)C[C@H]1CO
Reaction time: 5 h
Yield: 60 %

Procedure:
7-[(1R,3S,4S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]-N-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100. mg, 0.188 mmol) was dissolved in THF (0.900 mL) and pyridine (0.900 mL). Pyridine hydrofluoride (7 drops) was added and the reaction was stirred for 5 h. Additional pyridine hydrofluoride (3 drops) was added and the reaction was stirred for 2 h before being quenched with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted using EtOAc (3×10 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the title compound (47.0 mg, 50%). LC/MS: Rt=1.53 min, ES+ 417 (FA standard).
Reaction SMILES: [C:1]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[N:18]([CH3:28])[CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[N:18]([CH3:28])[CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CN(C)c2ccccc2NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)NC1CN(C)c2ccccc2N(CC(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice cold mixture of 84 mg of 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one, 15 mg of powdered potassium hydroxide and 6.5 mg of tetrabutylammonium bromide in 3 ml of dry tetrahydrofuran is treated with 32 mg of methyl bromoacetate. The reaction is allowed to stir for 3 hr at room temperature. At this time, the solution is filtered and concentrated and the residue dissolved in 20 ml of ethyl acetate. This is washed with 5 ml of water and dried over potassium carbonate. Concentration under reduced pressure affords 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-1-carbomethoxymethyl-5-methyl-1,3,4,5-tetrahydro-1,5-benzo diazepin-2-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:16])[C:11](OCC)=[O:12].CO.[CH3:19][NH2:20]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:16])[C:11]([NH:20][CH3:19])=[O:12]
Reactant: CCOC(=O)C(=O)c1ccccc1COC
Reactant: CN
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)C(=O)c1ccccc1COC
Reaction time: 2 h

Procedure:
28.3 g of the ethyl 2-(2-methoxymethyl-phenyl)-2-oxoacetate obtained in (1), 109 g of toluene, and 54.4 g of methanol were mixed, 28.6 g of a 40% aqueous methylamine solution was added while retaining at 25° C., and the mixture was retained at 25° C. for 2 hours. Thereafter, 54.4 g of water was added, 80 g of toluene were further added, this was allowed to stand still, and an organic layer was recovered. The organic layer was washed with 178 g of 5% hydrochloric acid, 54.4 g of an aqueous saturated sodium bicarbonate solution, and 54.4 g of water, respectively, and concentrated with an evaporator to obtain 12.0 g of 2-(2-methoxymethyl-phenyl)-N-methyl-2-oxo-acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 73 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:8][N:7]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][C:41](Cl)=[O:42])=[CH:35][CH:34]=1>ClCCl.C(Cl)(Cl)Cl>[CH2:39]([O:40][C:41]([N:12]([CH:13]([CH3:14])[CH3:15])[C@H:9]1[CH2:8][N:7]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:11][CH2:10]1)=[O:42])[C:36]1[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C[C@H]1CC[C@@H](NC(C)C)CN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@@H](N(C(=O)OCc2ccccc2)C(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2R,5R)-2-(2-ethoxy-2-oxoethyl)-5-(isopropylamino)piperidine-1-carboxylate (6.0 g) in dichloromethane (200 mL) was added diisopropylethylamine (19.1 mL), and thereto was further added dropwise under ice-cooling Z—Cl (13.0 mL) over a period of one hour. The mixture was stirred at room temperature for one hour, and then, the reaction solution was diluted with chloroform. The mixture was washed successively with an ice-cold aqueous potassium hydrogen sulfate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (8.9 g) as a pale brown oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C.C(OCC)(=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([Br:3])=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([Br:17])[CH:13]=3)=[CH:28][CH:29]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)cc1
Temperature: 60 °C

Procedure:
In a 250 ml one-neck flask provided with a reflux condenser, 990 mg (41.2 mmol) of NaH were suspended in 80 ml of dry DMF under protective gas. 10 g (30.8 mmol) of 3,6-dibromocarbazole in 80 ml of DMF were added dropwise to this reaction mixture at RT over a period of 20 minutes. A solution of 4-(tert-butyl)-benzyl bromide in 50 ml of DMF was subsequently added dropwise and the mixture was heated at 60° C. for 8 hours. After cooling to room temperature, 300 ml of water and 200 ml of ethyl acetate were carefully added. The organic phase was washed with 4×50 ml of H2O, then dried over MgSO4 and the solvents were removed under reduced pressure. The pure product was obtained by recrystallization from n-hexane. Yield: 11 g (78%); HPLC purity: 99.4%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:20][N:21](C=O)C>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-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCOCCc1cccc(C#N)c1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
Pd(Ph3P)4 (0.53 g) was added in one portion to tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] (3.00 g), and zinc cyanide (1.68 g) in DMF (35 mL) under nitrogen. The resulting mixture was stirred at 130° C. for 30 min. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through Celite. Isohexane (100 mL) was added and the mixture was washed with water (4×20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-20% ethyl acetate in isohexane to afford the subtitled compound (2.30 g). 1H NMR (300 MHz, CDCl3) δ 7.54-7.43 (m, 3H), 7.41-7.34 (m, 1H), 3.67 (t, J=6.3 Hz, 2H), 3.66 (t, J=6.6 Hz, 2H), 2.89 (t, J=6.5 Hz, 2H), 2.47 (t, J=6.3 Hz, 2H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[C:12]([CH3:25])=[N:13][N:14]2[C:19](NCCN)=[CH:18][C:17]([CH3:24])=[N:16][C:15]=12.O1CCC(=O)CC1.C([BH3-])#N.[Na+].[ClH:37]>CO.CCOCC.C(O)(=O)C>[Cl:37][C:19]1[N:14]2[N:13]=[C:12]([CH3:25])[C:11]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=3[Cl:10])=[C:15]2[N:16]=[C:17]([CH3:24])[CH:18]=1
Reactant: Cl
Reactant: COc1cc(Cl)c(-c2c(C)nn3c(NCCN)cc(C)nc23)c(Cl)c1
Agent: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(Cl)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(Cl)c1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution of N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine (3.32 g, 8.7 mmol) and tetrahydro-4H-pyran-4-one (1.8 g, 18 mmol) in methanol (60 mL)/acetic acid (1.6 g) was added sodium cyanoborohydride (1.1 g, 17 mmol), portionwise. After stirring 1 hour the reaction was concentrated under reduced pressure and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined extracts were dried (Na2SO4), concentrated under reduced pressure to give the crude product as a colorless foam (4.1 g, quant). A solution of the product in ether (150 mL) was treated with 1 M ethereal HCl which generated a precipitate that was collected by vacuum filtration to give the title compound (4.1 g, 94%) as a pink solid: +APcI MS (M+1)+464; 1H NMR (methanol-d4) δ: 7.14 (s, 2H), 6.38 (s, 1H), 4.03 (dd, 2H), 3.94 (br t, 2H), 3.86 (s, 3H), 3.50-3.38 (m, 5H), 2.51 (s, 3H), 2.26 (s, 3H), 2.05 (m, 2H), 1.68 (qd, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:12]=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][CH2:12][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1nc2ccccc2cc1Br
Reactant: NCc1ccccc1
Product: Brc1cc2ccccc2nc1CNCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 8, Step 2, using the following starting materials: 3-bromo-quinoline-2-carbaldehyde and benzylamine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28](/[C:29](=[CH:35]/[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])/[C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1>CO>[Cl:24][C:25]1[CH:33]=[C:32]2[NH:31][C:30](=[O:34])[C:29]3([CH:35]([CH2:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:28]2=[CH:27][CH:26]=1
Reactant: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)CC1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 110 °C
Yield: 34.8 %

Procedure:
To a mixture of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (0.25 g, 1 mmol) prepared in example 1b, and toluene (4 mL) was added E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (0.25 g, 1 mmol) prepared in example 1a. The reaction mixture was heated in a sealed tube under nitrogen at 110° C. for 18 h. The mixture was cooled to room temperature, and methanol (10 mL) was added. The mixture was concentrated and the residue was purified by chromatography (EtOAc/hexanes=2:1) to give racemic (2′S,3S,4′S)-6-chloro-2′-(3-chlorophenyl)-4′-(2,2-dimethylpropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a brown solid (Yield 0.15 g, 35%).
Reaction SMILES: Br[CH:2]1[CH2:5][C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:3]1.[I:10][C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]1[C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:5][CH:2]1[N:13]1[CH:12]=[C:11]([I:10])[CH:15]=[N:14]1
Reactant: BrC1CC2(C1)OCCO2
Reactant: Ic1cn[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1cnn(C2CC3(C2)OCCO3)c1
Temperature: 87.5 °C
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of 2-bromo-5,8-dioxa-spiro[3.4]octane (Compound 100F, 19 g, 100 mmol) and 4-iodopyrazole (38.6 g, 200 mmol) in DMF (100 mL) was added powdered K2CO3 (41.4 g, 300 mmol) and 18-crown-6 ether (5.3 g, 20 mmol). The reaction mixture was stirred at 85-90° C. for 2 days. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (4×100 mL). The combined organic layers were washed with brine and concentrated, the residue was purified by column chromatography (ethyl acetate/DCM: 5:95) to give 8.8 g (29%) of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole. 1H NMR (CDCl3, 300 MHz): δ=2.87-2.89 (m, 4H), 3.92-3.96 (m, 4H), 4.64-4.68 (m, 1H), 7.53 (s, 2H).