Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]([C:16]3[S:20][C:19]([CH:21]=[O:22])=[C:18]([CH3:23])[CH:17]=3)=[N:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C.Cl>C(#N)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]([C:16]3[S:20][C:19]([CH:21]=[O:22])=[C:18]([CH3:23])[CH:17]=3)=[N:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[O:9][CH2:31][CH2:32][OH:33])[CH3:2]
Reactant: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)s2)cc(C)c1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)s2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
To a suspension of 5-[5-(3-ethyl-4-hydroxy-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-3-methyl-thiophene-2-carbaldehyde (54 mg, 157 μmol) and K2CO3 (65 mg, 470 μmol) in acetonitrile (10 mL), (2-bromoethoxy)-tert.-butyl-dimethyl silane (66 mg, 274 μmol) is added. The mixture is stirred at 70° C. for 2 h before another portion of (2-bromoethoxy)-tert.-butyl-dimethyl silane (66 mg, 274 μmol) is added. Stirring is continued at 60° C. for 16 h. The mixture is cooled to rt, acidified by adding 1 N aq. HCl (2 mL) and stirred at rt for 10 min. The reaction mixture is concentrated to a volume of about 1 mL, is diluted with DMF (1.5 mL) and is then separated by prep. HPLC (XBridge Rp C18, 30×75 mm, eluting with a gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give 5-{5-[3-ethyl-4-(2-hydroxy-ethoxy)-5-methyl-phenyl]-[1,3,4]thiadiazol-2-yl}-3-methyl-thiophene-2-carbaldehyde (33 mg) as a pale yellow resin; LC-MS: tR=0.69 min; [M+1]+=429.06. b) The title compound (24 mg) is obtained as a colourless resin starting from the above 5-{5-[3-ethyl-4-(2-hydroxy-ethoxy)-5-methyl-phenyl]-[1,3,4]thiadiazol-2-yl}-3-methyl-thiophene-2-carbaldehyde (33 mg, 85 μmol) and dimethylamine (46 mg, 340 μmol); LC-MS*: tR=0.96 min; [M+1]+=418.01; 1H NMR (D6-DMSO): δ1.22 (t, J=7.5 Hz, 3H), 2.20 (s, 3H), 2.25 (s, 6H), 2.34 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 3.58 (s, 2H), 3.72-3.77 (m, 2H), 3.85 (t, J=4.5 Hz, 2H), 4.92 (t, J=5.5 Hz, 1H), 7.52 (s, 1H), 7.67 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 129 mg of the title compound (66%) as a yellow solid in 99.8% purity by HPLC (Rt: 4.72, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(OCC)C>[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
Hydrogen chloride gas was bubbled into an ice-bath cooled solution of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (4.50 g, 0.00783 mol, prepared as in 2005-0059670A1) in DCM (100 mL). The resulting suspension was stoppered and stirred at RT overnight, then diluted with diethyl ether (200 mL). The solid was collected by filtration, washed with diethyl ether, and dried to give the hydrochloride salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (4.01 g, 92%). Melting point 200° C. HPLC, C18 reverse phase, 10%-95% gradient of 0.1% TFA/CH3CN in 0.1% TFA/H2O during 22 minutes: 99.0% at 11.04 minutes. MS (APCI) M++1: calc'd, 448.2, found, 448.3. Anal. calc'd for C24H29N7O2.2.4H2O.1.85 HCl: C, 51.64; H, 6.44; N, 17.56, Cl (total), 11.75. Found: C, 51.31; H, 6.41; N, 17.20; Cl (total), 12.11.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:18][CH3:19])=[O:9])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C([O-])COc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(Cl)cc1
Reaction time: 96 h
Yield: 93 %

Procedure:
A solution of 4-chlorophenoxyacetate acid (Aldrich) (18.62 g, 99.8 mmoles) and concentrated sulfuric acid (Fisher) (2.5 mL) in ethanol (170 mL) was refluxed with stirring under a Drierite tube for 96 hours. The reaction solution was cooled in an ice-bath, and the volatiles were removed by spin evaporation in vacuo to a volume of about 100 mL. The liquid was dissolved in dichloromethane (225 mL) and washed with a solution of 5% aqueous sodium bicarbonate (4×100 mL) and finally with brine (1×50 mL). The solution was dried over sodium sulfate and spin evaporated in vacuo to give 19.97 g (93% yield) of ethyl 4-chlorophenoxyacetate as an amber liquid.
Reaction SMILES: O.[OH-].[Li+:3].[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:32]5[O:31][C:30]([C:33]([O:35]CC)=[O:34])=[CH:29][C:28]=5[CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5]>O1CCCC1.O>[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[C:32]5[O:31][C:30]([C:33]([O-:35])=[O:34])=[CH:29][C:28]=5[CH:27]=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].[Li+:3]
Reactant: CCOC(=O)c1cc2cccc(N3CCN(CCc4ccc5c(c4)CCN5C(C)=O)CC3)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCc2cc(CCN3CCN(c4cccc5cc(C(=O)[O-])oc45)CC3)ccc21
Temperature: 100 °C
Yield: 99.3 %

Procedure:
Lithium hydroxide monohydrate (0.087 g, 2.08 mmol) was added to a solution of ethyl 7-(4-(2-(1-acetylindolin-5-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (0.481 g, 1.04 mmol) in tetrahydrofuran (9 mL) and water (1 mL) and the reaction was heated at 100° C. for 35 min in a microwave oven. The solvents were evaporated and the material was dried in vacuum over P2O5 to give 0.454 g of the crude product. The crude material was used in the next step assuming quantitative yield without further purification. MS (ES+) m/z 434.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][CH:12]=[O:13])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H](CCO)CCN1C(=O)OCC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H](CC=O)CCN1C(=O)OCC

Procedure:
A solution of 0.991 g of trans 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol and 1.24 g pyridinium chlorochromate in 20 ml of methylene chloride is stirred under nitrogen for 4 hours. Mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (1:1) to yield trans 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]1[C:23]2[CH:24]=[C:25]([CH3:32])[C:26]([NH:28]C(=O)C)=[CH:27][C:22]=2[O:21][N:20]=1)([CH3:3])[CH3:2]>Cl.CC(O)=O.[OH-].[Na+]>[NH2:28][C:26]1[C:25]([CH3:32])=[CH:24][C:23]2[C:19]([CH2:18][CH2:17][C:5]3[S:6][C:7]4[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=4[C:4]=3[CH:1]([CH3:3])[CH3:2])=[N:20][O:21][C:22]=2[CH:27]=1
Reactant: CC(=O)Nc1cc2onc(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)c2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1N
Temperature: 25 °C
Yield: 67.8 %

Procedure:
The above-mentioned N-[3-[2-[3-Isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]ethyl]-5-methylbenzisoxazol-6-yl]acetamide (326 mg, 0.708 mmol) was dissolved in 1M HCl (3.0 mL) and AcOH (7.0 mL). The solution was heated under reflux for 23 hours. Then reaction mixture was cooled to room temperature, diluted with 4M NaOH, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 2:1) to give the title compound as a brown crystal (201 mg, yield: 68%).
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([O:24]C)=O.[NH3:31]>CO>[F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([NH2:31])=[O:24]
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)F

Procedure:
In a similar manner as described for example 38, 110 mg of methyl 3-{[2-(difluoromethoxy)benzyl]oxy}-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 20 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].Cl.[C:23]([O:27][NH2:28])([CH3:26])([CH3:25])[CH3:24].[NH4+].[Cl-]>C(OCC)(=O)C>[C:23]([O:27][NH:28][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:15][CH:14]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)ON
Reactant: O=C(O)CCCCOc1ccc(I)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)ONC(=O)CCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-(4-iodophenoxy)pentanoic acid (6.00 g, 18.8 mmol) and excess thionyl chloride was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was azeotroped three times with ethyl ether and then was taken up in THF. To the acid chloride solution was added an aqueous solution of O-tert-butylhydroxylamine (24 mmol; prepared by adding aqueous 3M NaOH to an aqueous solution of O-tert-butylhydroxylamine hydrochloride) and the cloudy solution was stirred for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and saturated aqueous NH4Cl. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give O-tert-butyl 5-(4-iodophenoxy)pentanohydroxamic acid (6.52 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][O:21]C3CCCCO3)=[O:19])[C:11](=[O:33])[CH:10]=2)=[CH:5][CH:4]=1>CC(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:29])=[O:30])[C:18]([NH:20][OH:21])=[O:19])[C:11](=[O:33])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: C[C@@](CCn1ccc(-c2ccc(F)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CC(C)O
Product: C[C@@](CCn1ccc(-c2ccc(F)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 M aqueous HCl (2.76 mL) was added slowly to a solution of (2R)-4-[4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (257 mg, 0.55 mmol) in 2-propanol (15 mL) at room temperature. The reaction was allowed to stir at room temperature overnight. After 18 hours the reaction was concentrated to afford a brown solid. Crude material was triturated in ethyl acetate (50 mL) for 1 hour; the solid was collected via filtration and washed with hexanes (20 mL). The solid was allowed to dry on the filter under high vacuum to afford an off-white solid. Yield 153 mg, 73%. MS (APCI) m/z 383.6 (M+H), 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 2.08-2.19 (m, 1H) 2.34-2.44 (m, 1H) 3.08 (s, 3H) 3.64-3.80 (m, 1H) 4.04-4.13 (m, 1H) 6.62 (dd, J=7.02, 2.15 Hz, 1H) 6.67 (d, J=1.95 Hz, 1H) 7.20-7.41 (m, 2H) 7.64-7.84 (m, 3H) 11.12 (br. s., 1H)
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and commercially available 5-bromo-2,4-difluorobenzenesulfonamide [CAS 287172-65-0] (247 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (310 mg, 58%). MS (ISP) 529.2 [(M+H)+]; mp 256-258° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:32])([F:15])[C:28]([F:29])([F:30])[F:31])=[CH:20][CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OCC(F)(F)C(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (133 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (174 mg, 0.57 mmol, Amine-20, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C([O:4][CH2:5][CH2:6][OH:7])(=O)C.C(N(CC)CC)C.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.ClCCl.CCCCCC.C(OCC)(=O)C>[Si:19]([O:4][CH2:5][CH2:6][OH:7])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.5 %

Procedure:
Commercially available 2-hydroxyethyl acetate (3.12 g, 30.0 mmol), triethylamine (4.6 ml, 33 mmol), and 4-(N,N-dimethylamino)pyridine (100 mg) were dissolved in dichloromethane (20 ml), then tert-butylchlorodiphenylsilane (8.65 g, 31.5 mmol) was added thereto at room temperature, and the mixture was stirred for 20 hours. The obtained solution was diluted with a mixed solvent of hexane-ethyl acetate (1:1), and then the resulting solution was washed with water and with an aqueous solution of sodium chloride. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (100 ml), and 28% sodium methoxide in methanol (3 ml) was added thereto at room temperature followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and a phosphate buffer solution (pH 7), then the organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the crude title compound (5.18 g, 57% gross yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([SH:13])[C:8]=2[CH3:12])[O:3]1.[OH-].[Na+].[N+:18]([CH3:21])([O-:20])=[O:19].Cl>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].CCOCC>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([S:13][CH2:21][N+:18]([O-:20])=[O:19])[C:8]=2[CH3:12])[O:3]1
Reactant: Cc1cc2c(c(C)c1S)CCC(C)(C)O2
Reactant: C[N+](=O)[O-]
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(c(C)c1SC[N+](=O)[O-])CCC(C)(C)O2
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
The thiol (B) was added to a solution of sodium hydroxide (2.8 g, 70 mM) in water (30 ml) and stirred vigorously for 30 minutes. Nitromethane (2.3 ml, 42.5 mM) was added, followed immediately by ether (75 ml). The reaction mixture was cooled to 15° C. in a cold water bath, then a solution of potassium ferricyanide (17.2 g, 52.3 mM) in water (43 ml) was added in a steady stream and the reaction mixture was stirred at ambient temperature overnight. The mixture was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water, brine, then dried (Na2SO4) and evaporated. The residual oil was purified by flash chromatography, eluting with hexane/toluene (4:1 v/v, increasing in polarity to 2:1 v/v), to give 2,2,5,7-tetramethyl-6-(nitromethylthio)chroman (3.1 g, 32% yield) as a gum; NMR: 1.3(6H,s), 1.82(2H,t), 2.4(6H, 2d), 2.61(2H,t), 5.18(2H,s), 6.6(1H,s).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[CH3:24][N:21]1[CH2:22][CH2:23][C:11]2[N:10]([CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[N:7][CH:6]=3)[OH:25])[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]=2[CH2:20]1
Reactant: CN(C)C=O
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(Br)nc2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 1-(6-bromo-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol (1 g, 2.5 mmol) in DMF (10 mL) were added Pd(PPh3)4 (0.173 g, 0.15 mmol) and zinc cyanide (585 mg, 5.0 mmol) and the reaction mixture was stirred at 150° C. for 2 h. The reaction mixture was cooled to RT, diluted with EtOAc (250 mL) and filtered. The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile (350 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.55 (s, 1H), 7.38 (d, 1H), 7.23 (d, 1H), 6.93 (s, 1H), 6.81 (s 1H), 6.74 (s,1H), 4.96 (m, 1H), 4.11 (dd, 2H), 3.29 (dd, 2H), 2.95 (m, 1H), 2.88 (m 1H), 2.86 (m, 2H), 2.5 (s, 6H). Separation by chiral HPLC provided enantiomers 140a and 140b.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][N:38]4C(=O)C5=CC=CC=C5C4=O)[CH:31]=3)[C:15](=[O:29])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[Cl:28])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:38][CH2:37][CH2:36][C:32]1[CH:31]=[C:30]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[Cl:28])[C:15]2=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3ccc(C(F)(F)F)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1cccc(N2C(=O)N(c3ccc(C(F)(F)F)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 32.3 %

Procedure:
A solution of 155 mg (0.23 mmol) of 7-anilino-3-(2-chloro-4-trifluoromethylphenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 20 ml of ethanol was treated with 0.3 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with hexane followed by filtration afforded 40 mg (32%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2-chloro-4-trifluoromethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 102° C.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].C([O:18][C:19](=O)[NH:20][C:21]1[S:22][C:23]([F:36])=[C:24]([CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:25]=1)(C)(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:10][C:19]([NH:20][C:21]1[S:22][C:23]([F:36])=[C:24]([CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:25]=1)=[O:18]
Reactant: COc1ccc(SCc2nc(NC(=O)OC(C)(C)C)sc2F)cc1
Reactant: NCc1cccc(F)c1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(SCc2nc(NC(=O)NCc3cccc(F)c3)sc2F)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 2 M trimethylaluminum in toluene (0.68 mL, 1.4 mmol) was treated with 3-fluorobenzylamine (0.16 mL, 1.4 mmol), followed by a solution of [5-fluoro-4-(4-methoxy-phenylsulfanylmethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (250 mg, 0.68 mmol), obtained above, in anhydrous toluene (3 mL). The resulting solution was heated at 80-100° C. for 3 hours. The cooled reaction mixture was hydrolyzed by sequential addition of: water (50 uL); 15% aqueous sodium hydroxide (50 uL); and water (150 uL). After stifling overnight, the granular aluminum salts were removed by filtration. The filtrate was concentrated and purified by silica gel chromatography (EtOAc) to afford Intermediate 106: 1-(3-fluoro-benzyl)-3-[5-fluoro-4-(4-methoxy-phenylsulfanylmethyl)-thiazol-2-yl]-urea as a pale yellow solid (168 mg, 59% yield).