Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:5][NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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.CCO>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=2[O:18][CH3:19])[CH2:5][NH:6][C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])=[CH:26][CH:25]=1
Reactant: COc1cc(CN[C@H](C)c2ccccc2)cc(Br)c1OC
Reactant: COc1ccc(B(O)O)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: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(CN[C@H](C)c3ccccc3)cc(OC)c2OC)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
To a mixture of (R)—N-(3-bromo-4,5-dimethoxybenzyl)-1-phenylethanamine 112 (1.1 g, 3.15 mmol), 4-methoxyphenylboronic acid (0.48 g, 3.15 mmol, Aldrich) and 2M Na2CO3 (5.0 mL) in 10 mL of toluene was added PPh3 (83 mg, 0.315 mmol) and Pd(PPh3)4 (0.364 g, 0.315 mmol) at room temp. under N2. The reaction mixture was then heated up to 80° C. under N2 atmosphere overnight. EtOH (4 mL) was added and the reaction was continued at 80° C. for 4 hours. The reaction was cooled to room temp. and diluted with 50 mL of EtOAc and 20 mL of sat'd. NaHCO3 aq. solution. The organic phase was separated, washed with 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10% EtOAc/hexane to 50% EtOAc/hexane) to afford light yellow oil as desired product (R)—N-(3-(4-Methoxyphenyl)-4,5-dimethoxybenzyl)-1-phenylethanamine 113 (0.5 g, 42%). MS (ESI, pos. ion) m/z: 378.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 10.0-10.2 (br, 2H), 6.8-7.5 (m, 9H), 6.8 (s, 1H); 6.7 (s, 1H), 3.9 (m, 1H); 3.7-3.8 (m, 1H), 3.8 (s, 3H); 3.7 (s, 3H); 3.4 (m, 1H), 3.2 (s, 3H), 1.7 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH:6]=[CH:5]2.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:25][CH2:26][O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30].S([O-])([O-])(=O)=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:29]([Si:28]([CH3:34])([CH3:33])[O:27][CH2:26][CH2:25][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:5]=[CH:6]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc2cc[nH]c2cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc2ccn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 352 mg of 5-methyl-6-nitroindole in 10 mL DMF was added drop wise 2.2 ml of 1M toluene solution of lithium hexamethyldisilazide. The solution was stirred for five minutes and 0.5 ml (1.1 equivalents) bromoethoxy dimethyl-t-butyl silane was added. The mixture was stirred at 0° C. for 30 minutes and then stirred for 4 hours at room temperature. Sulfate buffer (pH2) was added and the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to yield 300 mg of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indole.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22])[CH:16]=[O:17].S(=O)(=O)(O)O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]([C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)[OH:17])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Reactant: c1ccsc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cccs2)cc([N+](=O)[O-])c1OC
Reaction time: 0.5 h

Procedure:
18.8 ml of n-butyllithium solution (1.6M in hexane) are added dropwise at -50° within 10 minutes to 4.03 g of thiophene dissolved in 40 ml of tetrahydrofuran. After stirring at -50° for 30 minutes 6.3 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 100 ml of tetrahydrofuran are added dropwise within 30 minutes. The reaction mixture is stirred at -50° for 1 hour at 0° for 30 minutes and poured into 100 ml of 2N sulphuric acid. The mixture is extracted three times with 100 ml of ether each time; the combined ether phases are washed with sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenemethanol of m.p. 79°-81° (from methylene chloride/hexane).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:40][CH2:8][C:6]1[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C)c12
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CBr)c12
Temperature: 70 °C

Procedure:
6-Chloro-3-methoxy-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.5 g, 3.41 mmol) was dissolved in CCl4 (10 mL), charged with NBS (637 mg, 3.58 mmol) and AlBN (56.0 mg, 0.341 mmol), and heated to 70° C. overnight. The reaction was diluted with DCM (10 mL) and purified by flash chromatography (5-25% EtOAc/hexanes) to give 4-(bromomethyl)-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C27H21BrClN3O [M+1]+519. found 519.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][Cl:25])=[CH:20][N:19]=3)[CH:15]=2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:9]=1[CH2:37][C:38]([O:40]CC)=[O:39])=[O:7])[CH3:4].Cl>O.CCO>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][Cl:25])=[CH:20][N:19]=3)[CH:15]=2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:9]=1[CH2:37][C:38]([OH:40])=[O:39])=[O:7])[CH3:4]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(CCl)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(F)(F)F)cc2)c2ccc(Oc3ccc(CCl)cn3)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
NaOH (17 mg, 0.43 mmol) in water (5 mL) was slowly added to 5-(5-chloromethylpyridin-2-yloxy)-2-ethoxycarbonylmethyl-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (50 mg, 0.086 mmol, see step (a) above) in EtOH (15 mL). The mixture was stirred at rt for 48 h, neutralized by addition of HCl (aq), concentrated and purified by preparative TLC. Yield 35 mg (74%), mp 168-170° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8](/[CH:9]=[CH:10]/[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(/C=C/[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CO)cc1
Temperature: -78 °C
Yield: 98.2 %

Procedure:
To a solution of the product of Example 149B (1.0 g, 3.02 mmol) dissolved in dichloromethane (20 mL) and cooled to −78° C. was added diisobutylaluminum hydride (1.0M in dichloromethane, 10.56 mL, 10.56 mmol) dropwise and the resultant solution stirred at −78° C. for 10 minutes, the cooling bath was then removed and after the reaction reached room temperature it was maintained at this temperature for an additional 1 hour. The solution had acetone (1 mL) added then EtOAc added to it and the mixture extracted with aqueous sodium potassium tartrate solution. The organic extract was then dried, filtered, and concentrated to afford 0.9 g (98%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:5].[O-:12][C:13]#[N:14].[K+].Cl>O>[CH3:1][O:2][CH2:3][C@@H:4]([NH:5][C:13]([NH2:14])=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC[C@@H](N)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC[C@@H](NC(N)=O)c1ccccc1
Temperature: 100 °C

Procedure:
(S)-2-Methoxy-1-phenylethanamine (5.6 g, 37.0 mmol) and potassium cyanate (8.12 g, 100 mmol) were taken up in HCl (1 N, 40 mL, 40.0 mmol) and water (40 mL). The reaction mixture was heated to 100° C. for 3 h. Room temperature was attained, water was added, and the products extracted into EtOAc (×3) followed by 10% MeOH-DCM (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with Et2O to give (S)-1-(2-methoxy-1-phenylethyl)urea. MS ESI calc'd. for C10H14N2O2 [M+1]+ 195. found 195.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:17]1([C:41]2[C:42]([O:47][CH2:48][CH3:49])=[N:43][CH:44]=[CH:45][CH:46]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([I:26])[CH:24]=2)[N:19]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=2[O:38][CH3:39])(=[O:29])=[O:28])[C:18]1=[O:40]>ClCCl>[CH3:39][O:38][C:31]1[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]=1[S:27]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[C:17]([C:41]2[C:42]([O:47][CH2:48][CH3:49])=[N:43][CH:44]=[CH:45][CH:46]=2)([NH:15][C:12]2[CH:13]=[CH:14][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)[C:18]1=[O:40])(=[O:29])=[O:28]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOc1ncccc1C1(Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Solvent: ClCCl
Product: CCOc1ncccc1C1(Nc2ccc(N3CCN(CC)CC3)cc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 11.3 %

Procedure:
4-(4-Ethylpiperazin-1-yl)phenylamine (44 mg, 0.21 mmol) was added to a solution of 3-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-iodo-1,3-dihydroindol-2-one (110 mg, 0.18 mmol) in dichloromethane (15 ml). The reaction mixture was agitated in a Biotage microwave vial at 120° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. Purification by chromatography (silica gel, 0-8% methanol in dichloromethane) resulted in 16 mg of the title compound (11% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH:8]=[C:9]([C:15]([O:17]CC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:17]=[C:15]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:7][CH:8]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=CNc1cccnc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diphenyl ether (30 mL) at 250° C. was added a 1 mL diphenylether solution of diethyl [(pyridin-3-ylamino)methylidene]propanedioate (0.80 g, 3.0 mmol) dropwise over 5 minutes. After 30 minutes, the mixture was cooled to ambient temperature, diluted with hexanes (100 mL) and filtered. The solid was dried in vacuo, providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8](=[C:11]([O:14]C)[CH2:12][CH3:13])[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8](=[C:11]([OH:14])[CH2:12][CH3:13])[C:9]#[N:10])=[O:7])=[CH:16][CH:17]=1
Reactant: CCC(OC)=C(C#N)C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCC(O)=C(C#N)C(=O)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A two-phase mixture of 5.0 g. 2-(p-fluorobenzoyl)-3-methoxy-2-pentenonitrile in 50 ml. of chloroform is stirred with a 50 ml. solution of aqueous 1 N hydrochloric acid. After 24 hours, the organic phase is separated and evaporated. The residue is recrystallized from chloroform to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 99.9 %

Procedure:
Using general procedure A, 4-methoxyphenylamine (246 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (612 mg, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=[C:9]2[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]2=[O:16])=[CH:29]3)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with (5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: C[C:2]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)([CH2:21][C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[C:3]([NH:5][C@@:6]([CH3:20])([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1.O.CCOCC>[CH2:39]1[O:38][C:35]2[CH:36]=[CH:37][C:32]([CH2:31][CH:2]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:3]([NH:5][C@@:6]([CH3:20])([C:17]([OH:19])=[O:18])[CH2:7][C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][CH:9]=3)=[O:4])=[CH:33][C:34]=2[O:40]1
Reactant: CC(Cc1ccc2c(c1)OCO2)(Cc1ccc2c(c1)OCO2)C(=O)N[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@](Cc1c[nH]c2ccccc12)(NC(=O)C(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
A solution of 0.36 g (0.66 mmol) of methyl bis-(3,4-methylenedioxyphenylmethyl)acetyl-(α-methyl-D-tryptophan) in 10 mL MeOH and 2 mL THF was treated with a solution of 0.133 g (3.3 mmol) of NaOH in 2 mL H2O and the solution stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed twice with 1N HCl, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the product. This was dissolved in Et2O and the solvent removed under reduced pressure to give 0.28 g (82.3% yield) of the product as an amorphous white solid. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[C:2]=1[Cl:1])[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCOC(C(=O)N3CCOCC3)C2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCOC(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a round bottom flask charged with tert-butyl (2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)carbamate (91 mg, 0.202 mmol) was added dichloromethane (1076 μl) and TFA (269 μl). The reaction mixture was stirred at rt 3 h. Excess TFA was removed by concentration in vacuo. The crude residue was free based using a Phenomenex Strata 1 g SCX column. The column was flushed with 3 column volumes methanol and 3 column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo to provide 3-amino-4-chloro-5-(2-(morpholine-4-carbonyl)morpholino)benzonitrile (68 mg, 0.194 mmol, 96%)
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])[O:4][N:3]=1.[CH3:12][N:13]=[C:14]=[O:15]>O1CCCC1>[CH3:12][NH:13][C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])[O:4][N:3]=1)=[O:15]
Reactant: C#CC(C)(C)c1cc(N)no1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: C#CC(C)(C)c1cc(NC(=O)NC)no1

Procedure:
A solution of 7.5 g of 3C and 5 ml of methyl isocyanate in 50 ml of tetrahydrofuran was heated at 50°-60° C. for two days. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel, using as eluent a 1:4:20 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane, to give 1-methyl-3-(5-(1,1-dimethyl-2-propyn-1-yl)-1,2-oxazol-3-yl)urea (3D), as a white crystalline solid, m.p.: 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[C:38]([F:39])([F:40])[F:41])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-trifluoromethylbenzonitrile. The compound was purified by using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane to n-heptane/ethyl acetate (1:0 to 4:1 v/v) and subsequent purification by preparative HPLC using a Gemini column and a gradient of acetonitrile:water (containing 0.5% formic acid). Colorless foam (47%). MS (ES+): M+H: 573.2.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][C:17]=2[S:30]([NH2:33])(=[O:32])=[O:31])=O)[C:3]1=[O:34].Cl>[OH-].[K+]>[NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][C:17]=3[S:30](=[O:32])(=[O:31])[N:33]=2)[C:3]1=[O:34]
Reactant: Nn1c(=O)c(C(=O)Nc2ccc(OCc3ccccc3)cc2S(N)(=O)=O)c(O)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 125 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
The product of Example 304E (3.13 g, 6.51 mmol) was suspended in 10% potassium hydroxide solution (50 mL), heated at 125° C. for 24 hours then at 140° C. for 24 hours. The mixture was poured into ice and 1 M hydrochloric acid, filtered, and dried to give the title compound (2.03 g, 67%). MS (ESI−) m/z 461 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.18 (s, 2 H) 5.33 (s, 2 H) 7.06 (m, 1 H) 7.25 (m, 3 H) 7.43 (m, 6 H) 7.69 (d, J=7.72 Hz, 1 H) 8.06 (d, J=8.09 Hz, 1 H) 16.31 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.Cl.[C:24]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O.CCOC(C)=O>CC#N>[Cl:1][C:2]1[N:3]=[C:4]([NH:38][CH2:37][CH:34]2[CH2:35][CH2:36][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:32][CH2:33]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (244 mg, 0.520 mmol), 1-N—BOC-4-aminomethyl piperidine hydrochloride (130 mg, 0.520 mmol) and TEA (0.200 mL, 1.44 mmol) in CH3CN (6 mL) was stirred at room temperature for 16 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 4-((2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (336 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C(O)C.[ClH:46]>O1CCCC1>[ClH:46].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:26]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN2CCCC2)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and pyrrolidine (0.11 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Additional pyrrolidine (011 mL, 1.3 mmol) and sodium triacetoxyborohydride (0.30 g, 1.4 mmol) were added and the reaction was stirred under nitrogen for 6 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 4-(tert-butyl)-2-(pyrrolidin-1-ylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (0.18 g, 42% yield) as a white solid.