Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:9][N:8]([C:16](=[O:25])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:7][CH2:6]2.O.O.[Sn](Cl)Cl.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[NH2:13])[CH2:9][N:8]([C:16](=[O:25])[CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN1CCOCC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1N)CN(C(=O)CCN1CCOCC1)CC2
Reaction time: 16 h
Yield: 67.9 %

Procedure:
6-(methyloxy)-2-[3-(4-morpholinyl)propanoyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline (assumed 1.62 mmol from previous reaction) was dissolved in dimethylformamide (3.0 mL) and diluted with ethanol (10 mL). The solution was treated with tin (II) chloride dihydrate (2.2 g, 9.6 mmol, Aldrich), hydrochloric acid (1.0 mL, 1.0 mmol, 1 M in water), and stirred for 16 h. Excess saturated aqueous sodium bicarbonate was added carefully and the observed white suspension was stirred for 1 h. The mixture was filtered through celite. The filtrate was concentrated and purified by chromatography on SiO2 (dichloromethane to 20% methanol/dichloromethane) to give 6-(methyloxy)-2-[3-(4-morpholinyl)propanoyl]-1,2,3,4-tetrahydro-7-isoquinolinamine (350 mg, 1.10 mmol, 68% over two steps) which was slightly contaminated with DMF. 1H NMR (400 MHz, DMSO-d6) is complicated by amide rotomers d ppm 2.31-2.41 (m, 4 H), 2.52-2.71 (m, 6 H), 3.50-3.57 (m, 4 H), 3.57-3.62 (m, 2 H), 3.72 (s, 3 H), 4.37-4.47 (two singlets at 4.38 and 4.45, 2 H), 4.54-4.61 (two broad singlets at 4.56 and 4.59, 2 H), 6.38-6.41 (two singlets at 6.39 and 6.40, 1 H), 6.55-6.58 (two singlets at 6.56 and 6.57, 1 H); ESIMS (M+H)+=320.
Reaction SMILES: [H-].[Na+].CCOP(OCC)([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[C:26]=2[CH:37]=O)=[CH:21][CH:20]=1.O>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:35])[CH3:36])[C:26]=2/[CH:37]=[CH:8]/[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:21][CH:20]=1
Reactant: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 8 h

Procedure:
0.465 g (10.65 mmol) of sodium hydride (55%) are introduced into a 100 ml three-necked, round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel and nitrogen delivery line, and washed twice with 5 ml of pentane. The pentane is removed using a pipette and the sodium hydride is blown dry with nitrogen. 10 ml of THF, rendered absolute using sodium, are added, and 1.84 g (7.46 mmol) of diethyl (N-methoxy-N-methylcarbamoyl-methyl)phosphonate dissolved in 5 ml of THF are slowly added dropwise so that the temperature does not exceed 30° C. 1 g (3.55 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved in 10 ml of THF is then added dropwise and the clear, slightly yellow solution is stirred overnight. The reaction mixture is poured into 100 ml of water and extracted 3 times with 50 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate=2:1) and crystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([O:29][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH3:31])[C:9]([CH3:28])([CH3:27])[C:10](=[O:26])[CH:11]([CH3:25])[CH:12]([OH:24])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:45](OS(C(F)(F)F)(=O)=O)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([O:29][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH3:31])[C:9]([CH3:27])([CH3:28])[C:10](=[O:26])[CH:11]([CH3:25])[CH:12]([O:24][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O[Si](C)(C)C(C)(C)C)C(C)COCc1ccccc1
Reaction time: 2 h
Yield: 111.5 %

Procedure:
To a solution of 71a (4.1 mg, 7.6 μmol) and 2,6-lutidine (10.0 μL, 43.5 mmol) in CH2Cl2 (0.2 mL) at −78° C. was added TBSOTf (10.0 μL, 85.8 mmol). After 2 h, more, 6-lutidine (10.0 μL, 43.5 mmol) and TBSOTf (10.0 μL, 85.8 mmol) were added. After 6 h, the mixture was diluted with sat aq NaHCO3. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 91:9) to give 36 (5.4 mg, 82%) as a clear oil. Spectroscopic data agreed well with the reported values.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH2:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:4]=1)[CH3:2].Cl[C:16]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[F:25][C:23]1[C:22]([F:26])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:8][C:6]2[N:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)[CH:24]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: CCc1cc(N)n(-c2ccccn2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(Nc2cc(F)c(F)cc2C(=O)O)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A solution of 3-ethyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (9.41 g, 50.0 mmol), 2-chloro-4,5-difluorobenzoic acid (9.63 g, 50.0 mmol), copper acetate (II) (0.908 g, 5.00 mmol) and potassium carbonate (6.91 g, 50.0 mmol) in N,N-dimethylformamide (50 mL) was heated under reflux under an argon atmosphere for 2 hours. The solution was allowed to cool to room temperature, and poured into water. The solution was made weakly acidic by the addition of 1N hydrochloric acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give crude 4,5-difluoro-2-[[3-ethyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (11.3 g, 66% yield). A solution of the compound (11.0 g, 31.9 mmol) in phosphorous oxychloride (15 mL, 161 mmol) was heated under reflux for 2 hours. The solution was allowed to cool to room temperature, and poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (5.50 g, 50% yield).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])#[N:22]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccc(C#N)c2)c1
Yield: 49.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (193 mg, yield: 49.6%).
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1\[C:6](=[O:14])[NH:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:3].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)/[C:5](=[CH:4]/[N:2]([CH3:1])[CH3:3])/[C:6]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)/C=C1\C(=O)Nc2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)/C=C1\C(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one (iii-a, 626 mg, 3.33 mmol) in DMF (10 mL) was added NaH (151 mg, 6.29 mmol) and the reaction was stirred at RT. After 10 min, benzyl bromide (500 μL, 4.20 mmol) was added and the mixture was stirred under an atmosphere of Ar for 22 h. The reaction was quenched with a few drops of water and poured into a separatory funnel containing EtOAc (150 mL) and washed with water (2×100 mL), followed by brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hexane) to yield (3Z)-1-benzyl-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellow solid (iv-a, 660 mg, 71%). NH4OAc QC conditions. DAD Retention Time =1.71 min. M+H=279.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[CH:14][CH2:15][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:9]1[C:28]([CH3:29])([CH3:30])[CH:27]1[CH2:26][CH2:25][C:13]([CH3:12])=[CH:14][CH2:15][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCC=C(C)CCC1OC1(C)C
Temperature: -50 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of 2.59 g of m-chloroperbenzoic acid in 50 ml of methylene chloride was added to a solution of 3.6 g of the product of Step A in 50 ml of methylene chloride cooled to -50° C. and the mixture was held at -5° C. for 1 hour and was then poured into a saturated aqueous sodium bicarbonate solution. The organic phase was decanted and the aqueous phase was extracted with methylene chloride. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 7-3 benzene-ethyl acetate mixture to obtain 2.2 g of ethyl 10-epoxy-7,11-dimethyl-3-oxo- 6-dodecenoate in the form of a pale yellow oil with a refractive index of nD22 = 1.4662.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH:11]1([C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][NH:18]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+].[Cl:32][CH2:33][C:34](Cl)=[O:35]>CCOC(C)=O>[Cl:32][CH2:33][C:34]([N:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)CCN[C@@H]2C1CCCCC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCc2ccccc2[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (L)-tartrate (520 mg) was dissolved in EtOAc (10 mL) and saturated aqueous sodium bicarbonate (10 mL) was added thereto. Under ice-cooling, a solution of chloroacetyl chloride (0.14 mL) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring at room temperature for 1 hour. The reaction liquid was extracted with EtOAc and dried over magnesium sulfate to obtain (1R)-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (415 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-])=O.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[O:6][CH2:7][C:8]#[N:9]
Reactant: Cc1ccc(OCC#N)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(OCC#N)cc1N
Temperature: 70 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
(4-Methyl-3-nitrophenoxy)-acetonitrile (6.0 g) was dissolved in 120 ml of ethyl acetate and treated with 21.8 g of tin (II) chloride dihydrate; and the mixture was stirred at 70° C. for 2 hours. The mixture was cooled, poured into a saturated solution of sodium bicarbonate, extracted with ethyl acetate, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (7:3) to give 2.7 g of (3-amino-4-methylphenoxy)-acetonitrile. ##STR65##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][Zn+])=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(OC)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methoxy-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=492 [M+Na]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[OH-].[Na+].[Cl:6][C:7]1[S:8][C:9]([CH2:12]Cl)=[CH:10][N:11]=1>C(Cl)(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:6][C:7]1[S:8][C:9]([CH2:12][NH:3][CH2:1][CH3:2])=[CH:10][N:11]=1
Reactant: CCN
Reactant: ClCc1cnc(Cl)s1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCNCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 60˜70% aqueous solution of ethylamine (3.6 mL) and a 20% aqueous NaOH solution (8.0 mL) were added dropwise respectively into a solution of 2-chloro-5-chloromethylthiazole (3.40 g) in chloroform (40 mL), then benzyl triethyl ammonium chloride (0.1 g) was added. After stirring overnight at room temperature, the pH of the resulting mixture was adjusted to weak alkaline. The organic layer was separated while the aqueous layer was extracted with dichloromethane twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 2-chloro-5-ethylaminomethylthiazole 3.37 g as an oil in 95.2% purity. GC-MS: (M+) (EI, 70 eV, m/z) calc: 176. found: 176.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([C:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH:34]=5)=[N:24][N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Rh].CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[N:24][N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C5=CCN(C)CC5)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Rh]
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(C5CCN(C)CC5)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
A flask was charged with 5% w/w Rh/Al2O3 (20 mg, 9.6 μmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-6-yl)benzo[d]thiazol-6-yl)acetate (22.3 mg), and EtOH (absolute, 2 mL). The reaction was evacuated (vacuum) and backfilled from a balloon of H2, then stirred vigorously at 23° C. for 2.5 h. At this point, the reaction was treated with THF (1 mL), and 5 M aq NaOH (1 mL), then heated to 100° C. for 30 min. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C34H37ClN4O3S: 617.2, 619.2 (M+H+); Found: 617.4, 619.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.22 (s, 1H), 7.98-7.78 (m, 3H), 7.71 (d, J=8.4 Hz, 1H), 7.65-7.57 (m, 3H), 5.28 (s, 1H), 4.13 (s, 0.5 H, minor diastereomer), 4.09 (s, 2.5 H, major diastereomer), 3.73-3.60 (m, 2H), 3.54-3.37 (m, 2H), 3.29-3.18 (m, 2H), 2.97 (s, 2.5H, major diastereomer), 2.94 (s, 0.5H, minor diastereomer), 2.64 (s, 3H), 2.45-2.31 (m, 2H), 2.28-2.06 (m 1H), 0.99 (s, 9H).
Reaction SMILES: C(OC(=O)NCC1C=CC2N(CCC(C)C)C(CN3C4C(=CC=CC=4)C(=O)N(C4CC4)C3=O)=NC=2C=1)(C)(C)C.[CH:40]([C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][N:43]=1)=[CH2:41].[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]1[CH:81]=[CH:80][C:63]2[N:64]([CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74](=[O:79])[C:75]([CH3:78])([CH3:77])[CH3:76])[C:65]([CH2:67]Cl)=[N:66][C:62]=2[CH:61]=1)=[O:57])([CH3:54])([CH3:53])[CH3:52].Cl>>[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]1[CH:81]=[CH:80][C:63]2[N:64]([CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74](=[O:79])[C:75]([CH3:78])([CH3:77])[CH3:76])[C:65]([CH2:67][N:44]3[C:45]4[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:42]([CH:40]=[CH2:41])=[N:43]3)=[N:66][C:62]=2[CH:61]=1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(CCl)n2CCCCOC(=O)C(C)(C)C
Reactant: C=Cc1n[nH]c2ccccc12
Agent: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Product: C=Cc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCOC(=O)C(C)(C)C)c2ccccc12
Yield: 71 %

Procedure:
The procedure for the preparation of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed starting with 3-vinyl-1H-indazole (140 mg, 0.970 mmol) and 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-chloromethyl-benzoimidazol-1-yl]-butyl ester; HCl salt (474 mg, 0.614 mmol). After quenching with water, a gum formed. The water was decanted and the residue partitioned between diethyl ether and water. The layers were separated and the aqueous phase extracted with diethyl ether (2×40 mL). The combined organic phases were washed with water (twice), brine, and dried (MgSO4). Purification by flash chromatography (eluent hexane-acetone 2:3) afforded 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(3-vinyl-indazol-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (386 mg, 71%) as a colorless foam:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:25][CH2:26][CH3:27])[C:23]=1I)[CH2:12][C:13]1[C:14]([NH2:20])=[N:15][C:16]([NH2:19])=[N:17][CH:18]=1)[C:2]1C=CC=[CH:4][CH:3]=1.[N:28]1([CH2:34][C:35]2[S:39][C:38]([B])=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:25][CH2:26][CH3:27])[C:23]=2[C:38]2[S:39][C:35]([CH2:34][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:36][CH:37]=2)[CH2:12][C:13]2[C:14]([NH2:20])=[N:15][C:16]([NH2:19])=[N:17][CH:18]=2)[CH2:3][CH2:4]1
Reactant: [B]c1ccc(CN2CCOCC2)s1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCc2ccccc2)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1ccc(CN2CCOCC2)s1

Procedure:
Prepared analogously to example (2ac) starting from 5-(3-benzyloxy-5-ethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 6) (1.429 g; 3 mmol) and (5-morpholin-4-ylmethyl-thiophen-2-yl)-boron acid (681 mg; 3 mmol).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH3:13].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:20])[CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:17](=[O:19])[CH3:18])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(F)cc1)C(C)=O
Temperature: 15 °C

Procedure:
A suspension of potassium tert-butoxide (11.2 g) in anhydrous tetrahydrofuran (200 mL) at 0° C. was treated with a mixture of tert-butanol (0.2 mL) and 3-oxobutyric acid ethyl ester (12.7 mL). The mixture was warmed to 15° C. over a period of 40 minutes and a solution of 1-chloromethyl-4-fluorobenzene (11.9 mL) in tetrahydrofuran (40 mL) was added and the resulting mixture heated at 70° C. for 20 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by distillation under reduced pressure (boiling point, 102-104° C. at 0.42 mbar) to afford title compound as a colourless oil, 12.4 g.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:31])=[O:30])[N:25]([S:33]([CH3:36])(=[O:35])=[O:34])[C:24]([CH:37]([OH:41])[CH:38]([CH3:40])[CH3:39])=[CH:23]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:31])=[O:30])[N:25]([S:33]([CH3:36])(=[O:34])=[O:35])[C:24]([C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])=[CH:23]2)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1S(C)(=O)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-ol (2.3 g, 3.8 mmol) in dry CH2Cl2 (25 mL) was added Dess-Martin periodiane (1.94 g, 4.56 mmol) in one portion. The mixture was allowed to stir at rt for 2 h. The reaction was quenched with a solution of Na2S2O3 (5 g in 30 mL H2O) and sat. NaHCO3 solution (40 mL). The mixture was extracted with EtOAc (3×80 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with EtOAc/hexanes (2/8) to provide 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one (2.0 g, 86% yield). LC-MS m/z 612 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 8.03 (s, 1H), 7.70-7.68 (m, 4H), 7.46-7.36 (m, 6H), 7.22 (s, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 3.36 (m, 1H), 2.89 (s, 3H), 1.29 (d, J=6.8 Hz, 6H), 1.13 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 197.83, 141.53, 136.69, 136.05, 135.50, 135.04, 132.81, 131.14, 129.99, 127.88, 123.17, 117.12, 114.21, 62.87, 44.19, 44.03, 39.09, 26.88, 19.30, 18.41.