Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:23])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:23]
Reactant: COc1ccc2c(n1)CC(=O)N2CCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(n1)CC(=O)N2CCCO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a hydrogen pressure of 45 psi, 510 mg (1.63 mmol) of the compound obtained in Step C and 72 mg of palladium-on-carbon suspended in 10 ml of methanol are stirred for 15 hours at room temperature. After filtration over Celite and evaporation, the residue is hydrolysed with water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to yield the title compound in the form of a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:9]3=[O:30].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:30]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(Br)ccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2C12COc1cc(Br)ccc12
Yield: 89.4 %

Procedure:
A stirred solution of 6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1H)-one (2.5 g, 5.2 mmol), triethylsilane (5.0 mL) and trifluoroacetic acid (15.0 mL) was refluxed for 14 h. The solution was concentrated in vacuo and precipitated from hexanes to afford 6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.47 g, 89%) as a colorless solid: MS (ES+) m/z 316.1 (M+1), 318.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c(COc2ccc(C#N)cc2)nc2nc(C=O)ccc21

Procedure:
3.65 g (12.5 mMol) of 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-hydroxymethyl-imidazo[4,5-b]pyridine were dissolved in 500 ml dichloromethane and mixed with 15.0 g of manganese dioxide. After 96 hours at room temperature the mixture was filtered through kieselgur and the solvent was distilled off. The filtrate obtained was evaporated down, the crystalline precipitate was triturated with ether, suction filtered and dried.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:13][CH2:14][CH2:15][NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=1>C(OCC)(=O)C>[CH3:1][S:2]([NH:13][CH2:14][CH2:15][NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(Nc2nc(NCCN)ncc2C(N)=O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2nc(NCCNS(C)(=O)=O)ncc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 114 μl portion of methanesulfonyl chloride and 205 μl of triethylamine were added to a mixture of 382 mg of 2-(2-aminoethylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide with 10 ml of ethyl acetate, followed by stirring at room temperature for 3.5 hours. The reaction mixture was washed with water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. This was concentrated under a reduced pressure and the resulting residue was recrystallized from a mixed solvent of methanol and ethyl acetate to obtain 210 mg of 2-{[2-(methanesulfonylamino)ethyl]amino}-4-(3-methylanilino)pyrimidine-5-carboxamide (colorless crystals).
Reaction SMILES: Br[C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:38]1[N:42]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[N:41]=[CH:40][CH:39]=1)CCC>>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:9]2[N:10]=[C:5]3[C:4]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)=[C:3]([CH3:32])[C:2]([C:38]4[N:42]([C:43]5[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=5)[N:41]=[CH:40][CH:39]=4)=[CH:7][N:6]3[N:8]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1c(Br)cn2nc(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-2-(4-methanesulfonyl-benzyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 13, 50 mg, 0.095 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 100 mg, 0.218 mmol) using a similar method to that used in Example 1 (Step 4) (29 mg).
Reaction SMILES: [F:1][C:2]([O:6][C:7]([F:10])([F:9])[F:8])=[C:3]([F:5])[F:4].[Cl:11][C:12]1[C:13]([N:18]2[C:22]([C:23]([O:25][CH2:26]C)=[O:24])=[CH:21][C:20]([OH:28])=[N:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1.[OH-].[K+].CO>O.CS(C)=O>[Cl:11][C:12]1[C:13]([N:18]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]([O:28][C:3]([F:5])([F:4])[CH:2]([F:1])[O:6][C:7]([F:10])([F:9])[F:8])=[N:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(O)nn1-c1ncccc1Cl
Reactant: FC(F)=C(F)OC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Trifluoromethyl trifluorovinyl ether was blown into a mixture of 1.0 g of ethyl 1-(3-chloro-2-pyridinyl)-3-hydroxy-1H-pyrazole-5-carboxylate, 0.042 g of potassium hydroxide, 10 ml of methanol and 10 ml of dimethyl sulfoxide under ice-cooling. The resulting mixture was stirred at room temperature for 4 days. Water was poured into the reaction mixture, and the mixture was extracted with diethyl ether two times. The organic layers were combined, washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 1.32 g of methyl 1-(3-chloro-2-pyridinyl)-3-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]-1H-pyrazole-5-carboxylate of the formula:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)([OH:3])=O.[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:26][NH:27][C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)=[O:3])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C)c2cc(C(=O)O)c(=O)oc2c1
Reactant: NNC(=O)c1ccccc1
Product: COc1cc(C)c2cc(C(=O)NNC(=O)c3ccccc3)c(=O)oc2c1

Procedure:
Compound 210 was prepared following the preparation of compound 26 except that 3-carboxy-5-methyl-7-methoxy-coumarin reacted with benzoyl hydrazine to give the title compound 210.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:15][O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
Under ice cooling, 18.7 g of N-Boc-L-serine was dissolved in 200 ml of DMF and 13.25 g of solid K2CO3 was added and suspended for 15 minutes, and then 41.6 g (3.2 eq) of Mel was added, followed by stirring for 24 hours. After the reaction, the reaction solution was filtered through celite and concentrated. The residue was extracted by liquid separation using 400 ml of water and 150 ml×4 of ethyl acetate and dried over sodium sulfate. The ethyl acetate layer was concentrated and subjected to silica gel column chromatography to obtain 17.1 g (87.4%) of an N-Boc-L-serine methyl ester as a transparent oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12]>[Pd].CO>[F:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1c(F)cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
To a suspension of 1,5-difluoro-2-methyl-3-nitrobenzene (21.0 g, 121.4 mmol) and 10% Pd/C (2.0 g) was added MeOH (200 mL) carefully and the flask was evacuated. The reaction mixture was flushed with hydrogen under balloon pressure and stirred at RT for 2 h. The reaction mixture was filtered through Celite bed and evaporated in vacuo to afford 3,5-difluoro-2-methylbenzenamine (18.0 g, 97%) as a dark yellow liquid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:32])[C:13](=[O:31])[N:14]([C:15]4[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:32][N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[CH:19]=2)[C:13]1=[O:31]
Reactant: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1ccccc1
Product: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccccc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 134.1.1) and phenylboronic acid (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: tR 2.32 min (Method A); M+H=496 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.96-7.92 (m, 1H), 7.81-7.79 (m, 1H), 7.69-7.65 (m, 2H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 5.28-5.16 (m, 21-1), 3.59-3.43 (m, 7H), 2.40-2.29 (m, 4H), 2.20 (s, 3H), 1.92 (s, 3H))
Reaction SMILES: [CH3:1][C:2]1([CH2:6][S:7][CH2:8][C:9]2([CH3:13])[CH2:12][O:11][CH2:10]2)[CH2:5][O:4][CH2:3]1.C[OH:15]>O>[S:7]([CH2:6][C:2]1([CH3:1])[CH2:5][O:4][CH2:3]1)([CH2:8][C:9]1([CH3:13])[CH2:10][O:11][CH2:12]1)=[O:15]
Reactant: CO
Reactant: CC1(CSCC2(C)COC2)COC1
Solvent: O
Product: CC1(CS(=O)CC2(C)COC2)COC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A 1-L round-bottom flask was charged with a solution of 6 (14.9 g, 73.6 mmol) in MeOH (240 mL) and cooled to 0° C. A solution of NaIO4 (16.5 g, 77.3 mmol) in water (180 mL) was added via addition funnel over ˜15 min. The ice bath was removed and the slurry was warmed to rt. MeOH (2×50 mL, added 20 min apart) was added, and the mixture was stirred for 12 h at rt. The mixture was filtered through a fritted funnel, and the white precipitate was washed with MeOH. The combined filtrate and washings were concentrated in vacuo, and the concentrate was coevaporated with toluene (200 mL). CH2Cl2 (400 mL) was added to the residue, followed by MgSO4. The mixture was filtered, and the filtrate was concentrated in vacuo to afford crude 3 (15.82 g) as a yellow solid. To the flask containing the crude solid was added toluene (200 mL), and the slurry was heated to 60° C. to affect complete dissolution. Decolorizing carbon was added, and the mixture was filtered by gravity into a 1-L Erlenmeyer flask. To the colorless solution was slowly added distilled hexanes (˜100 mL total) until cloudiness/precipitation occurred. The mixture was allowed to stand at rt overnight. Upon filtration and drying under high vacuum, 3 (10.49 g) was collected as a white solid. Material recovered from the mother liquor was recrystallized to afford an additional 2.68 g of 3 as white solid for a total yield of 82%. Reported analytical data refer to that of the first crop: Mp 92.8-94.1° C.; IR (ATR) 2939, 2863, 1451, 1381, 1227, 1026, 971 cm−1; H NMR (400 MHz, CDCl3) δ 4.80 (d, J=6.0 Hz, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.50 (d, J=5.4 Hz, 2H), 4.45 (d, J=6.0 Hz, 2H), 3.38 (d, J=12.9 Hz, 2H), 2.75 (d, J=12.9 Hz, 2H), 1.61 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 82.4, 82.0, 61.9, 38.4, 23.4; HRMS (ES) m/z calc for C10H18O3NaS (M+Na) 241.0874. found 241.0885.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.25 g, 5.55 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in dichlormethane (30 mL) and triethylamine (1.20 mL) was added 4-chloro-benzoyl chloride (1.09 g, 6.21 mmol, 1.12 equiv; commercially available) and the reaction stirred at rt overnight. A solution of 1 M NaOH (10 mL) was added and the reaction mixture extracted with ethyl acetate. The combined organic phases were washed with water and a sat. solution of NaCl, dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was crystallized from a mixture of hexane/ethyl acetate yielding 0.71 g (44%) of the title compound as white crystals. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 1.85 (t, J=10.2 Hz, 2H), 2.45 (br s, 2H), 3.24 (t, J=11.8 Hz, 2H), 3.99 (br d, J=13.5 Hz, 2H), 6.87 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H). MS (ISP): 364.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8]CCC)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].O.O.[C:18]([O-])(=O)[CH3:19].[Zn+2:22].[C:23]([O-:26])(=[O:25])[CH3:24].[Na]>O>[CH2:23]([C:4]1[CH:3]=[C:2]([OH:1])[CH:13]=[CH:12][C:5]=1[C:6]([O-:8])=[O:7])[CH2:18][CH3:19].[CH2:5]([C:4]1[CH:3]=[C:2]([OH:1])[CH:13]=[CH:12][C:24]=1[C:23]([O-:26])=[O:25])[CH2:6][CH3:18].[Zn+2:22]
Reactant: CCCOC(=O)c1ccc(O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCCc1cc(O)ccc1C(=O)[O-]

Procedure:
To a suspension of 20.7 parts (0.155 mole) of propyl p-hydroxybenzoate in 40 parts of water that had been cooled to 0°-10° C. was slowly added a 50% aqueous sodium hydroxide solution until the pH of the resulting solution was 11.9. A solution of 12.6 parts (0.06 mole) of zinc acetate dihydrate in 200 parts of water was added to the sodium salt solution. The white precipitate that formed was separated by filtration, washed with cold water, and dried. There was obtained 23.9 parts of zinc bis(propyl p-hydroxybenzoate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30]([O:32]C(C)(C)C)=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>[Cl-]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30]([OH:32])=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)C2=CCN(C(=O)OC(C)(C)C)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)C2=CCN(C(=O)O)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The t-butyl 1,5-di-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylate (0.45 g, 0.8 mmol) is dissolved in chloride (1.5 mL) and cooled down in an ice bath. Trifluoroacetic acid (1.5 mL, 19.0 mmol is added and the resulting solution is stirred at 0° C. for 3 hours. The reaction mixture is warmed to room temperature and an additional 1 mL of trifluroacetic acid is added. The resulting solution is stirred for an additional hour and the mixture is concentrated under reduced pressure. The residue is carried forward without further purification. MS (ESI): 485 (M+H+), 502 (M+NH4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.[I:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[I:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene 25 (3 g, 11.1 mmol), and ρ-iodobenzoyl chloride in 65 mL of methylene chloride was added aluminum trichloride (2.1 g) in three portions and the reaction was stirred 3 hours. It was then poured into ice-water and extracted with methylene chloride. The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography with 3% ethyl acetate-hexanes as eluant the title compound (3.97 g) was obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]4[O:26][C:25]([CH3:28])([CH3:27])[CH:24]=[CH:23][C:18]4=3)[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]4[O:26][C:25]([CH3:28])([CH3:27])[CH:24]=[CH:23][C:18]4=3)[NH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C=Cc2c(ccc3[nH]c4c(c23)CCN(C(=O)c2ccccc2)CC4)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C=Cc2c(ccc3[nH]c4c(c23)CCN(Cc2ccccc2)CC4)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10-benzoyl-3,3-dimethyl-7,8,9,10,11,12-hexahydro-3H-azepino[4,5-b]pyrano[3,2-e]indole (0.115 g, 0.31 mmol) in tetrahydrofuran (5.0 mL) was added lithium aluminum hydride (0.125 g, 3.10 mmol). The resulted mixture was stirred at room temperature for 16 h. Water (0.13 mL), 15% sodium hydroxide solution (0.13 mL) and water (0.39 mL) were added sequentially. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to dryness. The residue was subjected to prep TLC (25% EtOAc/hexane, 1% Et3N) to afford 0.067 g (60%) of light yellow solid as the title compound: 1H NMR (300 MHz, CDCl3) δ 7.68, 7.47-7.30, 7.06-7.02, 6.69, 5.63, 3.85, 3.18-3.16, 3.05-2.88, 1.49; 13C NMR (DMSO-d6) δ 147.3, 139.5, 138.2, 130.8, 129.4, 129.2, 128.7, 127.5, 124.7, 120.9, 113.5, 113.2, 111.9, 110.0, 75.0, 61.4, 55.8, 54.0, 28.6, 27.4, 26.2; MS (ESI+) m/z 373 (M++H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[NH:4][C:3]1=[O:11].[CH3:12]I.[H-].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:12])[C:3]1=[O:11]
Reactant: COC(=O)C1CN(C)C(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CN(C)C(=O)N1C
Temperature: -10 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
Methyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1 g, 6.32 mmol) (prepared as described in step (iii) of Example 1, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) was dissolved in anhydrous tetrahydrofuran (10 ml), cooled to −10° C. under argon, and treated with methyl iodide (1.57 ml, 25.3 mmol). Sodium hydride (60% in oil, 0.24 g, 6.0 mmol) was then added in portions over a period of 15 minutes and the mixture was allowed to warm to room temperature and stirred for 18 hrs. The reaction mixture was then reduced in vacuo and the residue partitioned between ethyl acetate (40 ml) and brine (20 ml). The organic layer was separated, passed through a hydrophobic frit, and reduced in vacuo to give a yellow oil. This material was purified by automated flash silica gel column chromatography (Biotage SP4), eluting with 50% ethyl acetate in hexane (5 column volumes) and then with a gradient of 50-80% in hexane (15 column volumes), to give methyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (0.479 g) as a yellow oil which was used without further purification.
Reaction SMILES: [C:1]1(/[C:7](/[CH2:34][CH3:35])=[C:8](\[C:24]2[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]#[N:33])=[CH:26][CH:25]=2)/[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:40]=[N+:41]=[N-:42])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[N:33]1[NH:40][N:41]=[N:42][C:32]=1/[CH:31]=[CH:30]/[C:27]1[CH:26]=[CH:25][C:24](/[C:8](/[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[CH:12]3)=[C:7](\[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)/[CH2:34][CH3:35])=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC/C(=C(/c1ccc(/C=C/C#N)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC/C(=C(/c1ccc(/C=C/c2nn[nH]n2)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1

Procedure:
A 40 mL vial equipped with a magnetic stir bar was charged with (E)-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylonitrile (100 mg, 0.22 mmol), trimethylsilylazide (289 μL, 2.2 mmol), and di-n-butyltin oxide (11 mg, 0.04 mmol) in anhydrous toluene (2 mL). This mixture was degassed with 3 vacuum/N2 cycles, and then refluxed overnight. The reaction was poured onto silica and eluted with hexane (50 mL) and then 20% methanol in DCM (100 mL). The filtrate was concentrated to give the crude product that was purified on a silica gel column eluted with 0-15% methanol in DCM affording the title compound (49 mg, 45%). 1H NMR (DMSO-d6, 300 MHz): δ 8.13 (s, 1H), 7.74 (d, 1H), 7.66 (m, 1H), 7.49-7.36 (m, 3H), 7.29-7.13 (m, 7H), 6.91 (d, 2H), 5.87 (dd, 1H), 3.92-3.89 (m, 1H), 3.84-3.71 (m, 1H), 2.49-2.42 (m, 3H), 2.09-1.97 (m, 2H), 1.85-1.67 (m, 1H), 1.63-1.51 (m, 2H), 0.90 (t, 3H). LCMS: 503 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12]([N:14]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C@H:15]1[C:21](O)=[O:22])=O)(C)(C)C>C1COCC1>[CH3:12][N:14]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C@H:15]1[CH2:21][OH:22]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)CCC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1[C@H](CO)CCC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
Lithium aluminum hydride (312 mg, 8.2 mmol) was stirred in THF (35 mL) at 0° C. (S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidine-2-carboxylic acid (500 mg, 2.1 mmol) in THF (5 mL) was added dropwise over 15 min. The resulting mixture was stirred at rt for 1 h, and heated at 55° C. for 1 h. Another batch of lithium aluminum hydride (140 mg, 3.7 mmol) was added and the resulting mixture was heated at 60° C. for 2 h. LC-MS indicated partial conversion to the product. The reaction mixture was cooled to 0° C. and quenched with 0.5 mL of H2O, 0.5 mL of 10% NaOH, and 1.5 mL of H2O sequentially. The resulting mixture was stirred at rt for 30 min before it was filtered through a celite plug. The filtrate was evaporated under reduced pressure to give crude (S)-(1,5,5-trimethylpyrrolidin-2-yl)methanol (380 mg) as a clear oil. LC-MS (ESI) m/z 144 (M+H)+.