Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[N:16]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:19]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33].CO>C(Cl)Cl>[ClH:27].[ClH:33].[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[N:19]=[C:15]([C:11]3([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:17]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-dimethylamino-ethyl)-1H-imidazol-2-yl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.00 equiv; 1.68 mmol; 785.00 mg) in 5 mL DCM and slowly add hydrogen chloride (24.00 mmol; 6.00 mL of 4M in dioxane) at RT. After 5 min, the solution becomes cloudy then an oily white solid comes out of solution. Add 2 mL methanol to get the solid back in solution. At 30 min, HPLC shows 25% starting material. Add 1 mL additional HCl solution. After total of 2 h stirring at RT, concentrate under vacuum. Re-dissolve in DCM and evaporate under vacuum to a white solid; Dry the white solid in a vacuum oven at 45° C. to 900 mg of the title compound. ES(MS): (m/z)=367.0 (M+H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:23]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH2:34]([N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:20][CH:19]=1)[C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])[CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCc2ccccc21
Yield: 93.3 %

Procedure:
A solution of 59 mg (0.11 mmole) of 1-[N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl]indoline (from Step A), 20 μL of anisole, and 0.5 mL of anhydrous TFA was stirred at room temperature for 16 hours. The residue obtained after evaporation of excess TFA was flash chromatographed over silica gel (elution with 0.5% MeOH--CH2Cl2) to give 49 mg (89%) of the title compound as a hard gum, homogeneous by TLC (95:5 MeOH--CH2Cl2); FAB-MS m/e 478 (M+1)+.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[NH:59][C:60](=[O:63])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[NH:59][C:60](=[O:63])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:47][CH:48]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)[nH]c54)c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)[nH]c54)c3=O)cc2)CCC1
Yield: 75 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(2,6-dioxo-8-phenyl-1,2,3,6-tetrahydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a yellow solid (41 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.3 Hz, 1H), 7.63 (s, 1H), 7.53-7.49 (m, 2H), 7.44-7.38 (m, 3H), 7.35-7.30 (m, 2H), 7.22-7.19 (m, 2H), 7.14 (d, J=8.3 Hz, 1H), 7.01 (s, 1H), 2.50-2.43 (m, 2H), 2.32-2.22 (m, 2H), 2.12-2.01, (m, 1H), 1.78-1.68 (m, 1H). LCMS (Method E): RT=2.63 min, [M+H]+=424.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([CH2:23]O)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].P(Br)(Br)[Br:26]>ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([CH2:23][Br:26])[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(CO)c3c12
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(CBr)c3c12
Reaction time: 20 h

Procedure:
5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropyl ester (1.0 g) is dissolved in dichloromethane. A solution of 0.83 phosphorous tribromide in 10 ml of dichloromethane is added. After 20 hours the resulting precipitate is suctioned off. The yield is 1.0 g of yellow crystals with indeterminate melting point.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[C:5]([F:14])=[CH:4][C:3]=1[C@@H:15]([NH:17][S@@](C(C)(C)C)=O)[CH3:16].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[C:5]([F:14])=[CH:4][C:3]=1[C@@H:15]([NH2:17])[CH3:16]
Reactant: Cc1cn(-c2cc(F)c([C@H](C)N[S@](=O)C(C)(C)C)cc2F)cn1
Agent: Cl
Solvent: CO
Product: Cc1cn(-c2cc(F)c([C@H](C)N)cc2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of (R)—N—((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg) in MeOH (10 mL) was added dropwise HCl (732 μl, 2.93 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO3 solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na2SO4) and concentrated to give (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine (330 mg). LCMS (B) m/z 238.1 (M+H)+
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[C:16]([CH2:26][OH:27])[C:15]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=2)=[O:29])=[CH:14][N:13]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[Cl:38])[CH2:31][NH:30][C:28]([C:15]1[C:16]([CH2:26][OH:27])=[C:17]([OH:18])[C:12]([C:10]([NH:9][OH:8])=[O:11])=[N:13][CH:14]=1)=[O:29]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1cnc(C(=O)NO)c(O)c1CO
Yield: 4.7 %

Procedure:
Product 15 of example 15 (0.03 g, 0.330 mmol,) and 10% Pd/C (25 mg) catalyst were stirred in methanol (4.0 mL) under an atmosphere of hydrogen for 1 hour. The catalyst was filtered and the reaction mixture was concentrated under vacuum to give 0.006 g of N5-(3,4-dichlorobenzyl)-N2,3-dihydroxy-4-(hydroxymethyl)pyridine-2,5-dicarboxamide as a white solid; 1H-NMR (400 MHz, dmso): δ=13.01 (s, 1H), 12.0 (s, 1H), 9.51 (s 1H), 9.02 (t 1H), 8.11 (s, 1H), 7.60 (d 1H), 7.40 (m, 2H), 4.68 (s, 2H), 4.48 (s, 2H); MS-ESI m/z 386 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:14])[CH2:12][CH2:11][Cl:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: O=C(CCCl)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4-Dichloroaniline (25.5 grams), β-chloropropionyl chloride (20 grams) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3,4-dichlorophenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[C:32]([C:33](O)=[O:34])=[C:31]([CH3:36])[O:30][N:29]=1>>[CH3:27][C:28]1[C:32]([C:33]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:34])=[C:31]([CH3:36])[O:30][N:29]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: Cc1noc(C)c1C(=O)O
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5c(C)noc5C)c4)CC3)cccc2n1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 3,5-dimethyl-4-isoxazolecarboxylic acid.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][CH2:50][N:42]2[C:41]1=[O:51]>>[CH2:32]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][CH2:50][N:42]2[C:41]1=[O:51])=[O:10])[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])=[O:31])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N[C@H]1CCS[C@H]2CCCCN2C1=O
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Product: O=C(N[C@H]1CCCCN(c2ccccc2)C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCCCN2C1=O)Cc1ccccc1

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-2-oxo-1-phenylazepan-3-yl)-N6-((4S,10aS)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (20 mg, 0.039 mmol) and Intermediate 40 (10 mg, 0.051 mmol) to give a white solid (16 mg, 58% yield). Anal. Calcd. for C41H50N4O4S m/z 694.4. found: 695.3 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (dd, J=18.7, 7.1 Hz, 2H), 7.35 (t, J=7.8 Hz, 2H), 7.29-7.03 (m, 11H), 5.60 (s, 1H), 5.04-4.85 (m, 1H), 4.76-4.59 (m, 1H), 4.08 (d, J=13.2 Hz, 1H), 3.95 (dd, J=15.3, 11.5 Hz, 1H), 3.52 (d, J=15.9 Hz, 1H), 3.07 (t, J=11.3 Hz, 1H), 2.87-2.35 (m, 11H), 2.08-1.01 (m, 17H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)O)=[CH:5][CH:4]=1.[OH-].[Na+].[H][H]>[Rh].C(O)C>[ClH:2].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: OC(c1ccc(Cl)c2ccccc12)C1CCNCC1
Agent: [Rh]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(CC2CCNCC2)c2ccccc12

Procedure:
To 250 ml of 6N hydrochloric acid is added 27.6 (0.1 mole) of α-(4-chloro-1-naphthyl)-4-piperidinemethanol and enough 95% ethanol to form a clear solution. The solution is refluxed for 18 hours, cooled, and made basic with 10% sodium hydroxide, extracted into toluene, and the organic phase washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is dissolved in acetic acid and shaken with hydrogen gas in a Parr apparatus in the presence of 0.5 g of rhodium/carbon at room temperature until 0.1 mole of hydrogen is taken up. The catalyst is filtered off, an excess of alcoholic hydrogen chloride is added and the solution concentrated in vacuo. The residue is recrystallized from methanol to yield 4-[(4-chloro-1-naphthyl)methyl]piperidine hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[O:12][CH2:13][CH:14]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH3:15]>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[O:12][CH2:13][CH:14]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH3:15]
Reactant: CC(COc1c([N+](=O)[O-])ccc(F)c1F)OC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CC(COc1c(N)ccc(F)c1F)OC1CCCCO1
Reaction time: 1 h

Procedure:
To a solution of 1.82 g of the compound obtained in Example 1 dissolved in 50 ml of ethanol was added 500 mg of 5% palladium on charcoal. Catalytic reduction was carried out under atmospheric pressure for about 1 hour. The catalyst was removed by filtration, and the solvent was removed under reduced pressure to yield the titled compound. This product was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([NH2:14])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:14][CH:2]([CH3:1])[CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=[CH:6]2)=[CH:27][CH:28]=1
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: CC(N)CCn1cnc2ccccc21
Solvent: CO
Product: CC(CCn1cnc2ccccc21)NCC(O)COc1ccc(CC(N)=O)cc1

Procedure:
A mixture of 1.65 grams of α-methyl-1H-benzimidazole-1-propanamine and 1.82 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 6 ml. of 95 percent methanol was refluxed for 19 hours. The solvent was evaporated from the mixture and the residual solid was triturated several times with ether. The solid was then dried and chromatographed on a silica gel column using methanol. The fractions containing the desired product were determined by thin-layer chromatography and combined. The solvent was then evaporated to leave a residual oil which solidified on cooling to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-α-methyl-1H-benzimidazole-1-propanamine melting at about 139°-142° C. This compound has the following structural formula. ##STR18##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[C:29]#[N:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH2:29][NH2:30])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2C#N)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2CN)CC1

Procedure:
To 288 mg (0.7 mmol) of 4-(3-benzylamino-2-cyano-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 7 mL tetrahydrofuran was added 1.4 mL (2 eq., 1.4 mmol, 1M in tetrahydrofuran)borane. The mixture was refluxed 10 hours and quenched with methanol, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to yield crude 4-(2-aminomethyl-3-benzylamino-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, which was used directly in the following step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:50][CH:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:51])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (635 mg, 2.6 mmol) was heated at 140° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, dichloromethane:methanol, 50:1) and then further purified by prep-HPLC to afford (4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (30 mg, 7.1%).
Reaction SMILES: O=C(Cl)OC(Cl)(Cl)Cl.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[NH:20][CH2:21][C:22]1[C:23]([NH:30][CH3:31])=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=1.CCN(CC)CC.[C:39]([O-:42])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[N:20]1[CH2:21][C:22]2[C:23](=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=2)[N:30]([CH3:31])[C:39]1=[O:42]
Reactant: O=C([O-])[O-]
Reactant: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])c(F)cc1Cl)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of diphosgene (2.1 mL, 6.8 mmol) in anhydrous dioxane (30 mL) was added a solution of 5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (2.2 g, 6.2 mmol) and Et3N (1.32 g, 13 mmol) in anhydrous dioxane (30 mL) at 0° C. After complete addition, the resulting mixture was stirred at 50° C. overnight. Water was added and the mixture was basified with saturated Na2CO3 solution. The mixture was concentrated in vacuo and the residue was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residual solid was washed with ether and dried to afford 3-(2-chloro-4-fluoro-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.4 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, J=8 Hz, 1 H), 8.26 (s, 1 H), 8.08 (d, J=12 Hz, 1 H), 4.82 (d, J=16 Hz, 1 H), 4.57 (d, J=16 Hz, 1 H), 3.29 (s, 3 H), 2.50 (s, 3 H); MS (ESI) m/z: 384.1[M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](OC)=[O:21])[CH:18]=2)[CH:13]=[CH:12]1>C1(C)C=CC=CC=1>[OH:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][N:11]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
Diisobutylaluminum hydride (1M in toluene, 12 mL, 12 mmol) was added to a solution of 1-tert-butyl 6-methyl 1H-indole-1,6-dicarboxylate (1.38 g, 5.00 mmol) in toluene (15 mL) at −50° C. over 10 minutes. After being stirred at −50° C. for 30 minutes, the reaction was quenched with methanol (2.5 mL) and water (2.5 mL). The resulting precipitate was filtered off, and the filtrate was evaporated. The residue was purified by silica gel chromatography, eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford tert-butyl 6-(hydroxymethyl)-1H-indole-1-carboxylate (815 mg, 55% yield) as an oil. LCMS (ESI) m/z 174.3 [M+H-18-56]+, 230.3 [M+H-18]+.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([O:19][C:20]2[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)([CH3:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCOC=O>ClCCCl>[Br:26][C:24]1[CH:23]=[CH:22][C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)=[C:20]([CH:25]=1)[O:19][C:16]1([CH3:18])[CH2:15][NH:14][CH2:17]1
Reactant: CC1(Oc2cc(Br)ccc2OCc2cccc(Cl)c2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=COCCCl
Solvent: ClCCCl
Product: CC1(Oc2cc(Br)ccc2OCc2cccc(Cl)c2)CNC1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
The title compound from Step B (60 mg) was dissolved in DCE (10 mL) and chloroethylformate (0.2 mmol) was added. The mixture was heated at 80-100° C. for 1 h and concentrated. The residue was dissolved in MeOH (3 mL) and heated at 150° C. in a microwave reactor for another 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (30 mg). MS (ESI): mass calcd. for C17H17BrClNO2, 381.0; m/z found, 382.0 [M+H]+. 1H NMR (CDCl3): 7.43-7.23 (m, 4H), 7.12-7.06 (m, 1H), 6.86-6.78 (m, 2H), 5.12 (s, 2H), 4.24-4.16 (m, 2H), 3.78-3.67 (m, 2H), 1.67 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cccnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyridin-3-yl-benzylamino)-methyl]-phenoxy}acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.59 (d, 1H), 7.89 (m, 3H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 3H), 7.17 (d, 2H), 7.10 (t, 1H), 6.74 (m, 1H), 6.64 (d, 1H), 6.58 (d, 1H), 4.37 (s, 2H), 4.34 (s, 2H), 4.32 (s, 2H), 1.48 (s, 9H); MS 545 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[C:19](=O)(O)[O-].[Na+]>CO>[CH3:19][O:12][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2
Yield: 97.8 %

Procedure:
A solution of 19.6 g (109 mmol) of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (J. Chem. Soc., 3445, 1957) in 400 mL of MeOH containing 4 mL of H2SO4 was refluxed overnight. Sodium bicarbonate (18 g) was added, the solvent was removed and the residue was triturated several times with Et2O. The washes were combined, filtered through anhyd MgSO4 and evaporated to yield 20.7 g of the title compound as a pale yellow oil: mass spectrum (electron impact, m/e): 194.