Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([C:31]([O:33]CC)=[O:32])[CH2:9][CH:8]([C:10]2([CH2:17][CH:18]([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)[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH2:7]1)=[O:5])C>[OH-].[Na+]>[C:4]([C:6]1([C:31]([OH:33])=[O:32])[CH2:9][CH:8]([C:10]2([CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(C2(CC(c3ccccc3)c3ccccc3)NC(=O)NC2=O)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(CC(c2ccccc2)c2ccccc2)(C2CC(C(=O)O)(C(=O)O)C2)N1
Temperature: 70 °C

Procedure:
A stirred mixture of 5-[3,3-di(ethoxycarbonyl) cyclobutyl]-5-(2,2-diphenylethyl)imidazolidine-2,4-dione (1.7 mmol) in 1M sodium hydroxide (17 ml) was heated to 70° C. for 2 hours. The cooled solution was filtered and the filtrate acidified with 5M hydrochloric acid (4 ml). The mixture was extracted with diethyl ether (30 ml) ethanol (3 ml) to give the title product as a white foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1>CC(=O)CC>[Cl:7][C:8]1[N:9]=[N:10][C:11]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCC(C)=O
Product: Clc1ccc(N2CCNCC2)nn1
Temperature: 62 °C
Yield: 80.9 %

Procedure:
Piperazine (20.0 g, 232 mmol) and 3,6-dichloropyridazine (34.6 g, 232 mmol) were mixed with 2-butanone and heated at 62° C. for 16 h. The reaction mixture was cooled to room temperature and the precipitated product filtered and washed with 2-butanone. The solid was redissolved in DCM (250 mL), filtered and the filtrate evaporated. The solid was dried in vacuo to yield 37.3 g, 81% 3-chloro-6-piperazin-1-ylpyridazine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[F:12].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22].[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O.Cl.C1COCC1.CO>[C:9]([C:5]1[CH:4]=[C:3]([F:12])[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[C:7]([F:8])[CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(F)c(N)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 317.2 %

Procedure:
To a solution of 1-(4-amino-3,5-difluoro-phenyl)-ethanone (2.35 g, 13.73 mmol) and Et3N (2 mL) in CH2Cl2 (10 mL) was added dropwise MsCl (2.34 mL, 2.34 mmol) at 0° C. The mixture was stirred for 3 hours at room temperature. The mixture was then diluted with EtOAc and 1N-HCl. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the following reaction. The crude residue was dissolved in THF (8 mL), after then was added 1N NaOH (4 mL) and CH3OH (4 mL) to the solution. After stirred for 5 hrs at room temperature, the mixture was diluted with EtOAc and 1N-HCl. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to afford N-(4-acetyl-2,6-difluoro-phenyl)-methanesulfonamide (1.85 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(F)cc(C)c1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
To a solution of (E1) and cesium carbonate (1.5 eq.) in DMF (0.25 M) at RT was added methyl iodide (1.0 eq.). After the mixture was stirred for 18 h, brine was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The yellow solid was used in the next step without purification. 1H NMR (400 MHz, DMSO, 300K) δ 7.63 (2H, m), 3.83 (3H, s), 2.29 (3H, s).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[O:5][CH:6]=1.C([Li])CCC.[NH:16]1[C:24](=[O:25])[C:22](=[O:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]>>[O:5]1[CH:6]=[C:2]([C:22]2([OH:23])[C:20](=[O:21])[NH:19][C:17](=[O:18])[NH:16][C:24]2=[O:25])[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]1=2
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1coc2ccccc12
Agent: [Li]CCCC
Product: O=C1NC(=O)C(O)(c2coc3ccccc23)C(=O)N1

Procedure:
3-Bromobenzo[b]furan [Mason et al., J. Chem. Soc., p. 3150 (1931)] is reacted with n-butyl lithium and then with alloxan, following the procedure of Example 5, to yield 5-(3-benzo[b]furyl)-5-hydroxy-2,4,6(1H,3H,5H)pyrimidinetrione.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[C:22](Br)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:12][C:13]1[C:22]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(CO)cc2)c1N
Yield: 45.7 %

Procedure:
A mixture of 4-(hydroxymethyl)phenylboronic acid (2.35 g, 15.5 mmol), methyl 3-amino-2,6-dibromoisonicotinate (4.0 g, 12.9 mmol), tetrakistriphenylphosphine palladium(0) (0.895 g, 0.774 mmol), sodium carbonate (3.28 g, 31.0 mmol) was flushed with nitrogen and toluene (32.3 mL), and MeOH (10.75 mL) were added. The reaction was heated at reflux under nitrogen for 24 hr. It was partitioned between EtOAc and water. The organic phase was washed with brine, dried with sodium sulfate, and the solvents removed. The organic phase was washed with brine, dried with sodium sulfate and the solvent removed. The residue was chromatographed (step gradient elution with DCM containing 0 to 20% EtOAc afforded methyl 3-amino-6-bromo-2-(4-(hydroxymethyl)phenyl)isonicotinate (1.99 g, 5.90 mmol, 46% yield) as a yellow fluffy solid. MS (ESI) m/z 336.8 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.80 (1H, s), 7.61 (2H, d, J=8.24 Hz), 7.48 (2H, d, J=7.93 Hz), 5.94 (2H, br. s.), 4.75 (2H, d, J=5.80 Hz), 3.92 (3H, s), 1.72 (1H, t, J=5.80 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH3:18])[CH2:10][C:11](OC(C)(C)C)=[O:12].[BH4-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:10][CH2:11][OH:12])[CH3:18]
Reactant: CC(C)(C)OC(=O)C[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(F)c1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](C)(CCO)c1cccc(F)c1Cl
Reaction time: 0.67 h
Yield: 100.2 %

Procedure:
To a solution of (5)-tert-butyl 3-(2-chloro-3-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate (8.75 g, 22.33 mmol) in tetrahydrofuran (100 mL) was added lithium borohydride, 2.0M in THF (29.9 mL, 59.8 mmol) dropwise, followed by MeOH (7.05 mL, 174 mmol). The reaction was stirred for 40 min and was carefully quenched by the addition of saturated ammonium chloride (75 mL), followed by water (100 mL) and EtOAc. The separated organic phase was washed with brine, dried over sodium sulfate and filtered to give (R)-N-((S)-2-(2-chloro-3-fluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide as a white solid (7.2 g, 100% yield). MS m/z=322 [M+H]+. Calculated for C14H21ClFNO2S: 321.8.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:17]2[C@@:13]([CH3:26])([C@@H:14]([C@:18]([OH:25])([CH3:24])[CH2:19][C:20](=[CH2:23])[CH2:21]O)[CH2:15][CH2:16]2)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:47]>CC#N>[Cl:47][CH2:21][C:20](=[CH2:23])[CH2:19][C@@:18]([C@@H:14]1[C@:13]2([CH3:26])[C@H:17]([C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11][CH2:12]2)[CH2:16][CH2:15]1)([OH:25])[CH3:24]
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=C(CO)C[C@](C)(O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]21C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C=C(CCl)C[C@](C)(O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]21C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of 8 (82 mg, 0.2 mmol), Ph3P (85 mg, 3.32 mmol), CCl4 (54 mg, 0.35 mmol, dried with CaCl2), and CH3CN (2 mL, dried with CaH2) was stirred for 30 min under argon. The mixture was flash chromatographed (SiO2, 2.5×5 cm. 5% EtOAc-hexanes) to give 9 (70 mg, 77%). This unstable compound was immediately used in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH2:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH:11][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(Br)cc(Cl)cc1C(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Br)cc(Cl)cc1C(C)Nc1ncnc2c1ncn2C1CCCCO1
Yield: 98.3 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-methoxyphenyl)ethanamine (2.2 g, 8.5 mmol) in ethanol (69 mL), was treated with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.6 g, 13 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) and heated at reflux overnight. The reaction mixture was cooled, poured into sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using acetonitrile in dichloromethane (5%-10%) and then ethyl acetate in hexanes (60%-100%) gave the desired product (3.9 g, 98%). LCMS for C19H22BrClN5O2 (M+H)+: m/z=466.1, 468.1. Found: 466.0, 468.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccccc1Oc1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A vessel containing 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.35 mmol), 2-methyl-phenol (38 mg, 0.42 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos) (5 mg, 0.01 mmol), Pd(OAc)2 (1.6 mg, 0.007 mmol) and potassium phosphate (150 mg, 0.70 mmol) in toluene (2 mL) was evacuated and flushed with nitrogen. The mixture was stirred at 110° C. overnight then were allowed to cool and then partitioned between EtOAc and water. The organic extract was washed with brine, dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2; gradient elution with 0-10% EtOAc in petrol) gave title compound (89 mg) {MS: [M+H]+=355} as an inseparable mixture with starting material.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>>[NH2:20][C:19]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=2[CH3:11])[N:10]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: Cc1c(Cl)cccc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Product: Cc1c(Cl)cccc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
(3-Chloro-2-methylphenyl)hydrazine hydrochloride (CAS no. 65208-12-0) (9 g, 46.61 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (60 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The resultant oil was suspended in MeOH (100 mL) under nitrogen at −5° C. 2-(Ethoxymethylene)malononitrile (5.69 g, 46.61 mmol) was added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product(6.33 g, 58.4%). 1H NMR (400 MHz, DMSO) δ 2.02 (3H, s), 6.57 (2H, s), 7.25-7.32 (1H, m), 7.37 (1H, t), 7.58-7.64 (1H, m), 7.77 (1H); m/z (ES+) (M+H)+=233.28; HPLC tR=1.89 min.
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O>CCOC(C)=O>[ClH:1].[ClH:1].[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCc1ccc2c(n1)NCCC2
Reaction time: 0.5 h

Procedure:
HCl gas was rapidly bubbled through a solution of 11-7 (2.5 g, 8.6 mmol) in EtOAc (100 ml) at 0° C. for 10 minutes. After 30 minutes, the solution was purged with argon for 30 minutes. The solution was concentrated and then azeotroped with CH3CN to give the amine 11-8 as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (72 mg, yield 90%).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:13])=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[C:14]1([C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(Cl)Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:1][C:2]3[C:3](=[C:4]4[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]4=[CH:11][CH:12]=3)[O:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2c1ccc(O)c2O
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Product: O=C1NC(=O)c2c1ccc1c2OC(c2ccccc2)(c2ccccc2)O1
Temperature: 160 °C

Procedure:
A suspension of the dihydroxyphthalimide from e) (350 mg) in diphenyldichloromethane (4 g) was heated at 160° C. for 3 hours. The resultant solution was cooled and washed with petroleum ether (3×10 ml). The petrol phase separated to give a brown oil which was collected and triturated under diethyl ether (5 ml) to give as a chestnut brown solid, diphenylmethylenedioxyphthalimide (300 mg); NMR (DMSO-d6) 7.5(m,12H); 11.05(s,1H). Cooling of the petrol phase afforded a second fraction of the phthalimide (250 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[C:3]([CH3:20])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCC(O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-3-(4-hydroxypiperidin-1-yl)-2-methoxy-4-methylphenyl]ethanone (15 mg, 0.050 mmol), ammonium acetate (39 mg, 0.50 mmol) and sodium cyanoborohydride (6 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (7 mg, 50%). LCMS calculated for C15H24ClN2O2 (M+H)+: m/z=299.1. found: 299.1.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[CH:11]=2)=[O:7]>C(O)C.C(OC(=O)C)C.[Pd]>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH2:17])[CH:11]=2)=[O:7]
Reactant: CN(C)CCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCNC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 82.9 mg (0.3 mmole) 125 in a mixture of ethanol/ethylacetate 1:1 10% Pd/C (40 mg) was added. The flask was flushed 3 times with hydrogen and filled with hydrogen at 30 to 35 psi. The suspension was stirred vigorously at room temperature for 30 minutes. The catalyst was filtered off, the filtrate was evaporated in vacuo to dryness. The solid 126 was used for the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>CN(C=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>[CH3:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([CH3:14])([CH3:13])[C:8]1=[O:12]
Reactant: CN1C(=O)C(C)(C)c2cccc(Br)c21
Reactant: C=CC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc2c1N(C)C(=O)C2(C)C
Temperature: 180 °C

Procedure:
A mixture of 7-bromo-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one from Step A (112 mg, 0.44 mmol), ethyl acrylate (0.238 mL, 2.20 mmol), triethylamine (0.124 mL, 0.88 mmol), and (PPh3)4Pd (51 mg, 0.044 mmol) in DMF (1.5 mL) was heated at 180° C. in a microwave reactor for 4 h. The reaction mixture was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 60:40, to give the title compound. MS: m/z=274 (M+1).
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14].[OH-].[Na+]>Cl.O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([I:1])[C:5]=1[NH2:14]
Reactant: ClI
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(Cl)cc(C(F)(F)F)cc1I
Temperature: 50 °C
Yield: 97.1 %

Procedure:
Iodine monochloride (17.2 g, 108 mmol) in hydrochloric acid (36%, 21.4 g) and water (35 mL) was added dropwise to 2-chloro-4-(trifluoromethyl)benzenamine (20.0 g, 102 mmol) in hydrochloric acid (36%, 20.7 g) and water (140 mL). The mixture was warmed to 50° C. for a total of 8 h. Sodium hydroxide (50%, 33.5 g, 419 mmol) was added to the mixture at room temperature. The mixture was extracted with dichloromethane (2×250 mL), and the extracts were dried and evaporated to give the product as an oil (31.83 g, 97% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CO.[BH4-].[Na+]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([CH:20]([OH:22])[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)O)s3)s2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.5 %

Procedure:
To a solution of Example 3A (320 mg, 0.89 mmol) in a mixture of 1:1 methanol:tetrahydrofuran (40 mL) was added sodium borohydride (67.5 mg, 1.78 mmol) and stirred at room temperature for 2.5 hours. The reaction mixture was quenched with acetone, the solvent removed in vacuum and the residue dissolved in dichloromethane. The organic phase was washed with water and brine, dried over magnesium sulfate filtered and evaporated, to produce the title compound (317 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.29 (m, 3H) 6.82-6.97 (m, 4H) 502-5.16 (m, 1H) 4.43-4.61 (heptet, J=6.25 Hz, 1H) 1.60 (d, J=6.62 Hz, 3H) 1.35 (d, J=6.25 Hz, 6H). MS (DCI): m/z 362 (M+H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=2)[NH:4][CH:3]=1.C(N(CC)CC)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:24]1([S:30]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1cc(-c2cnc3[nH]cc(I)c3c2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cn1
Reaction time: 2 h
Yield: 90 %

Procedure:
The 3-iodo-5-(1-methylpyrazol-4-yl)-7-azaindole prepared in accordance with WO 2008155000 (34 g) is suspended in 350 ml of dichloromethane, and 43.5 ml of triethylamine and 2.6 g of 4-(dimethylamino)pyridine are added. 17.5 ml of benzenesulfonyl chloride which has previously been diluted with 150 of dichloromethane are added to this mixture. After 2 h, the reaction is complete. The organic phase is extracted three times with water, and the organic phase is dried over sodium sulfate. After removal of the solvent, the residue is taken up in ethyl acetate, the precipitate is filtered off, rinsed with ethyl acetate, and the product is dried in air to give 44 g (90%) of beige crystals; (Rt: 2.467 min; M+H+: 464.9).