Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:21](OC)([CH3:23])[CH3:22].CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH3:22][C:21]1([CH3:23])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][O:14]1
Reactant: COC(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: COC(=O)[C@H]1COC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of methyl N-[(benzyloxy)carbonyl]-D-serinate (1013 mg) and 2,2-dimethoxypropane (4166 mg) in acetone (20 mL) was added pyridin-1-ium 4-methylbenzenesulfonate (201 mg) at room temperature, and the reaction mixture was stirred at 60° C. overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (860 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11]CC)=[O:10])=[CH:4][N:3]=1.[OH-].[Na+].Cl>>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(C)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc(C(=O)O)c(C)n1
Temperature: 25 °C

Procedure:
Intermediate 54 (7.3 g, 40.5 mmol) dissolved in sodium hydroxide solution (4.86 g, 121.6 mmol in 10 ml water) and refluxed. The reaction mixture was cooled to rt and acidified with con HCl to obtain the solid. Solid that obtained was filtered and dried to obtain the title compound quantitatively as an yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.5 (bs, 1H), 8.93 (s, 1H), 2.66 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36](O)=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[O:43]=[S:44]1(=[O:56])[CH2:49][CH2:48][CH:47]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:46][CH2:45]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([CH3:35])[CH:21]=3)[C:36]([N:53]3[CH2:54][CH2:55][N:50]([CH:47]4[CH2:46][CH2:45][S:44](=[O:43])(=[O:56])[CH2:49][CH2:48]4)[CH2:51][CH2:52]3)=[O:37])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCS(=O)(=O)CC3)CC2)cc(C)c1OCc1ccccc1

Procedure:
Prepared analogously to Example 1i from 150 mg (0.26 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1g) and 57 mg (0.26 mmol) 1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48](Cl)=[O:49])[N:47]=1>C(Cl)Cl>[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[O:49])[N:47]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: Nc1cc(-c2cncc(NS(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}benzenesulfonamide (100 mg) was dissolved in DCM (5 ml) and pyridine (0.024 ml) was added. The reaction was stirred at RT for 2 min before 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added. The reaction was stirred at RT for 18 h. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (10 mg) was added and stirring continued for 2 h at RT. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added and the reaction stirred at RT for 18 h before being quenched with water. DCM was added and the reaction was passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:MeOH (1:1, v/v, 1 ml) and purified by MDAP (method E). The desired dried intermediate was dissolved in MeOH and 2M NaOH (1 ml) was added. The reaction was stirred at RT for 30 min. The reaction was neutralised with 2M HCl (aq) then evaporated to dryness. The residue was dissolved in MeOH and loaded onto a SCX-2 SPE cartridge pre-conditioned with MeOH. After eluting with MeOH then 10% NH3 in MeOH, the basic fraction was evaporated to dryness to give the title compound (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[S:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[Br:13].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O>CCO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]2[S:12][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[Br:13]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1Br
Solvent: CCO
Product: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Temperature: 70 °C
Yield: 81.9 %

Procedure:
A mixture of 2-bromo-5-carbamothioylbenzoic acid methyl ester (which may be prepared as described for Intermediate 5; 13.7 g, 50 mmol) and 2-bromo-3′,4′-dichloroacetophenone (available from Aldrich Chemical Company, Inc.; 13.5 g, 50.5 mmol) in EtOH (200 mL) was heated at 70° C. overnight. The solid was filtered off to give 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (18.14 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[H-].[Na+].BrC[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C1COCC1>[C:37]([O:36][C:34](=[O:35])[CH2:33][NH:28][C:25]1[CH:26]=[CH:27][C:20]2[O:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][N:12]=4)[S:23][C:22]=3[C:21]=2[N:24]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CC(C)(C)OC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 0 °C
Yield: 88 %

Procedure:
Compound 134 (800 mg, 2.0 mmol) was dissolved in THF (20 mL). It was stirred at 0° C. and NaH (58 mg, 2.4 mmol) was added. Then the mixture was warmed to r.t. and stirred for further 0.5 h. The mixture was cooled to 0° C. and tert-butyl 3-bromopropanoate (502 mg, 2.4 mmol) was added. Later, it was warmed to 80° C. for 2 h. The reaction mixture was filtered to gather the solution. Then water was added into the solution. It was extracted by DCM (20 mL×3). The combined organics were dried over Na2SO4, concentrated in vacuo, and separated by prep TLC (DCM) to give {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-acetic acid tert-butyl ester (900 mg, yield: 90%)1HNMR (CDCl3, 400 MHz): δ 8.04 (s, 1H), 7.45-7.52 (m, 1H), 7.42 (s, 1H), 7.06-6.93 (m, 4H). 4.25-4.15 (m, 2H), 4.08-3.99 (m, 2H), 3.06 (s, 2H), 1.38 (s, 9H). LC-MS (ESI): m/z=512 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:20])[CH3:23]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 52.3 %

Procedure:
Beginning with 6.0 mg (0.026 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 2.96 mg (0.0273 mMol) ethyl chloroformate, 4.1 mg (52%) of the title compound were recovered.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[F:12][C:13]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])([F:23])[C:14]([F:22])([F:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[F:12][C:13]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][OH:27])([F:23])[C:14]([F:22])([F:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccccc1C(F)(F)C(F)(F)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride, 530 mg. (0.0139 mole), is weighed under nitrogen, transferred to a dry-nitrogen-flushed reaction flask, and suspended in 15 ml. of absolute ether. A solution of 4.15 g. (0.0139 mole) of 2-(α,α,β,β-tetrafluorophenethyl)benzoic acid in 35 ml. of absolute ether is added dropwise. The mixture is stirred at room temperature for 30 minutes and allowed to stand overnight in a nitrogen atmosphere. Hydrolysis is effected by the dropwise addition of 1 ml. of water. The precipitate is removed by filtration, and washed with ether. Evaporation of the dried ethereal filtrate under reduced pressure leaves the product as a white solid, m.p. 80°-81° C. A sample for analysis is sublimed at 70° C. and 0.1 mm.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CN([CH:27]=[O:28])C>C1COCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: COc1ccncc1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccncc1C=O
Temperature: -23 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a stirred solution of 1.7 M t-butyl lithium in THF (35.0 mL, 59.6 mmol) with THF (150 mL) at −78° C. was added dropwise 2-bromomesitylene (4.6 mL, 29.8 mmol). After stirring for 1 h, 4-methoxy-pyridine (2.5 g, 22.9 mmol) was added dropwise. This solution was warmed to −23° C. and stirred for 3 h and then cooled to −78° C. again. DMF (2.7 mL, 34.4 mmol) was added and the solution was stirred at −78° C. for 1 h. The reaction was quenched at this temperature with brine (150 mL) and extracted with ether. The combined ether was dried over K2CO3 and evaporated in vacuo. The residue was chromatographed with 50%-80% EtOAc/hexanes to give 2.1 g (65%) of 4-methoxy-pyridine-3-carbaldehyde as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccccc1F)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, off-white solid, m.p.91° C. and MS: m/e=323 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(C(=O)OC)c1
Yield: 100 %

Procedure:
Using General Procedure A: A solution of 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.402 g, 1.50 mmol), 4-bromomethyl-isophthalic acid dimethyl ester (0.603 g, 2.10 mmol), KI (63 mg, 0.38 mmol), and DIPEA (0.60 mL, 3.44 mmol) in DMF (7.5 mL) was heated at 60 ° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 710 mg (99%) of COMPOUND 52 as a white solid. 1H NMR (CDCl3) δ 1.63-1.77 (m, 3H), 2.09 (br s, 1H), 2.34-2.52 (m, 8H), 3.84 (s, 6H), 4.02 (s, 2H), 4.18 (d, 2H, J=11.1 Hz), 6.82 (dd, 2H, J=4.8, 7.5 Hz), 7.14 (d, 2H, J=7.5 Hz), 7.72 (s, 2H), 7.92 (s, 1H), 8.22 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 19.32, 25.66, 28.30, 50.13, 52.23, 52.36, 67.14, 122.20, 126.83, 128.07, 130.49, 131.08, 131.33, 132.14, 138.08, 146.90, 149.71, 159.50, 166.88, 167.23; ES-MS m/z 474 (M+H). Anal. Calcd. For C28H31N3O4.0.3H2O: C, 70.21; H, 6.65; N, 8.77. Found: C, 70.17; H, 6.60; N, 8.72.
Reaction SMILES: [C:1](#N)C.[F:4][C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C(=O)([O-])[O-].[K+].[K+].CI>O>[F:4][C:5]1[C:6]([O:13][CH3:1])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9]
Reactant: CC#N
Reactant: O=Cc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1c(F)cccc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To an acetonitrile (50 mL) solution containing 3.01 g (21.5 mmol) of commercially available 3-fluoro-2-hydroxybenzaldehyde were added 5.92 g (42.8 mmol) of potassium carbonate and 6.66 mL (107 mmol) of methyl iodide, and the mixture was stirred at 90° C. for 3 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 3.22 g of a crude product of 3-fluoro-2-methoxybenzaldehyde.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.CO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH-].[Na+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[O:23]=[C:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:24])[CH:2]=[O:1])=[CH:12]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)C=O
Reaction time: 0.5 h

Procedure:
1.0 g. of 21-hydroxy-4-pregnene-3,20-dione is dissolved in 125 ml. of methanol and combined with a solution of 250 mg. of copper(II) acetate in 125 ml. of methanol. For 30 minutes, air is passed through the solution, and the latter is then combined with a solution of 500 mg. of ethylenediaminetetraacetic acid in 50 ml. of water, adjusted to pH 9 with 1N sodium hydroxide solution. The mixture is concentrated under vacuum at 40° C. and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated under vacuum. As the residue, 1.1 g. of 3,20-dioxo-4-pregnen-21-al is obtained as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](O)[CH3:16]>>[OH:1][C:2]1[N:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:15][CH3:16])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1cc(S(=O)(=O)O)cnc1O
Product: CCOC(=O)c1cc(S(=O)(=O)O)cnc1O
Temperature: 80 °C

Procedure:
2-Hydroxy-5-sulfonicotinic acid (500 g, 2.28 mol) was dissolved in ethanol (2.5 L) with stirring and heated to 80° C. After 30 mins 0.5 L of solvent was distilled off, then replaced with fresh ethanol (0.5 L) and taken back to 80° C. After a further 60 mins 1.0 L of solvent was distilled off, then replaced with fresh ethanol (1.0 L) and taken back to 80° C. After a further 60 mins 1.0 L of solvent was distilled off, the reaction cooled to 22° C. and stirred for 16 hr.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][OH:20].[H-].[Na+]>CS(C)=O>[F:12][C:3]1[CH:4]=[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]2=[N:7][C:2]=1[O:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: OCc1ccccn1
Reactant: Cn1ccc2cc(F)c(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ccc2cc(F)c(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a stirred solution of 6-chloro-5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (1.276 g, 6.91 mmol) and 2-pyridine methanol (0.800 mL, 8.29 mmol) in dimethyl sulphoxide (10 mL), under a nitrogen atmosphere, is added 60% sodium hydride (0.332 g, 8.29 mmol) portionwise, and reaction stirred at room temperature overnight. The reaction is then heated to 80° C. for 1 h, cooled to room temperature and further 60% sodium hydride (0.090 g, 2.32 mmol) added. After 30 minutes of stirring at room temperature, the reaction is further heated at 80° C. for 30 minutes. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 2×30 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 80% EtOAc in hexane, to give the title compound as a light green oil (1.445 g, 5.62 mmol). MS (m/z): 258 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH2:24]([O:23][C:21]([CH:20]1[CH2:26][CH2:27][N:17]([CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH:9]=2)[CH2:18][CH2:19]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3-formyl-phenyl)-carbamic acid tert-butyl ester (Schadendorf T et al., Tetrahedron Letters (2007), 48(51), 9044-9047), (1 g, 4.52 mmol), ethyl isonipecotate (800 mg, 5.09 mmol) and TEA (0.7 mL, 5 mmol) in MeOH (50 mL) is treated with acetic acid (1.03 mL, 18 mmol) and stirred at RT for 2 h. Sodium cyanoborohydride (398 mg, 6.33 mmol) is added at once and the reaction mixture is stirred for 18 h at RT. Water (5 mL) is added to the mixture and the solvents are evaporated. The residue is partitioned between diethyl ether (50 mL) and aqueous 0.1N HCl (50 mL). The aqueous phase is separated, washed twice with diethyl ether (25 mL) and basified with 1N NaOH solution (10 mL). The aqueous phase is extracted three times with DCM (3×50 mL). The combined organic phases are dried over MgSO4 and evaporated. The title compound is obtained as a thick oil; LC-MS A: tR=0.71 min; [M+H]+=363.48.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].CO[C:12](OC)(OC)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:13]([C:12]1[N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[C:6](=[O:7])[NH:8][N:9]=1)[CH2:14][CH3:15]
Reactant: CCCC(OC)(OC)OC
Reactant: NNC(=O)c1ncc[nH]1
Solvent: CCO
Product: CCCc1n[nH]c(=O)c2nccn12
Temperature: 25 °C

Procedure:
A mixture of 37.0 gm. of 2-imidazolecarboxylic acid hydrazide, prepared by the method of U.S. Pat. No. 3,600,399, 2.5 liters of ethanol and 325 ml. of trimethylorthobutyrate is refluxed overnight and evaporated to a solid. This solid is ground, added to 400 ml. of diphenyl ether and heated in an oil bath at 220°-245° C. for 30 minutes. The mixture is cooled to room temperature and crystallized by the addition of 100 ml. of petroleum ether. The solid is collected, washed twice with petroleum ether, recrystallized from 300 ml. of a hot mixture of ethanol and methanol and treated with charcoal giving 53.5 gm. of the desired final product, m.p. 153°-159° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:3]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:16])[CH:5]=[C:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)c1c[nH]c(=O)c(Br)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CN(C)C(=O)c1cc(Br)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (100 mg, 0.408 mmol) and iodomethane (57.9 mg, 0.408 mmol) in DMSO (3 mL) was added potassium carbonate (56.4 mg, 0.408 mmol). The mixture was stirred at room temperature overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 10-90% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The product was dried under vacuum to give the title compound.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:23].O1CCOCC1>>[ClH:23].[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2=CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (700 mg, 2.27 mmol, intermediate N) and HCl in dioxane (4.0 ml, 16 mmol) was stirred at rt for 3 h. The crude mass was concentrated under vacuum and the solid residue was washed with 3×10 ml of DCM to remove non-polar impurities. The desired salt was collected as a fine solid (480 mg, 93%). LCMS (ES-API) m/z 190.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 6.08-5.98 (m, 1H), 5.11 (s, 1H), 3.97 (br. s., 1H), 3.52 (s, 1H), 3.32 (s, 3H), 2.47-2.37 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:30])[CH:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][S:2][C:3](=[NH:30])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After adding 100 g of manganese dioxide to a solution of 27.2 g of the crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester in 100 ml of ethyl acetate, the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (23.8 g, crude product) as a brown solid.