Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]([C@H:17]1[N:22]2[CH2:23][CH2:24][NH:25][CH2:26][C@H:21]2[CH2:20][N:19]([CH2:27][C:28]2[CH:33]=[C:32]([N:34]3[C:38]([C:39]([F:42])([F:41])[F:40])=[N:37][N:36]=[N:35]3)[CH:31]=[CH:30][C:29]=2[O:43][CH3:44])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:45]1([C:50](O)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C>[ClH:1].[ClH:1].[CH:4]([C@H:17]1[N:22]2[CH2:23][CH2:24][N:25]([C:50]([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:51])[CH2:26][C@H:21]2[CH2:20][N:19]([CH2:27][C:28]2[CH:33]=[C:32]([N:34]3[C:38]([C:39]([F:42])([F:41])[F:40])=[N:37][N:36]=[N:35]3)[CH:31]=[CH:30][C:29]=2[O:43][CH3:44])[CH2:18]1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CNCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CN(C(=O)C3CCCC3)CCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4R,9aS)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine trihydrochloride (80 mg), cyclopentanecarboxylic acid (16.9 μl), 1-hydroxybenzotriazole hydrate (23 mg), and triethylamine (79 μl) in dichloromethane (1 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride at room temperature. After stirring at room temperature overnight, the mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with preparative TLC (methanol/chloroform=1/9) to give an oil. To a solution of the oil in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate (0.2 ml) and hexane (20 ml). After stirring for 30 minutes, the precipitate was collected by filtration and dried under reduced pressure at 50° C. for 5 hours to give (4R,9aR)-4-benzhydryl-8-cyclopentanecarbonyl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (63.9 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[O:10]CC)=[CH:4][C:3]=1[O:16][CH3:17].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CCOC(=O)NCCc1ccc(Cl)c(OC)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1Cl)C(=O)NCC2
Temperature: 110 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
Ethyl 4-chloro-3-methoxyphenethylcarbamate (I-86c: 500 mg, 1.7063 mmol) in POCl3 (10 mL) was reacted with P2O5 (484 mg, 3.41 mmol). The resulting mixture was stirred at 110° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 200 mg of the product (55.5% yield).
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.[O:12]=[S:13]1(=[O:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][N:16]4[CH2:17][CH2:18][S:13](=[O:27])(=[O:12])[CH2:14][CH2:15]4)=[CH:21][CH:22]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ncc2ccc(Br)n2n1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Product: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1

Procedure:
(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1,1-dioxo-1 $1(6)-thiomorpholin-4-ylmethyl)-phenyl]-amine was prepared from 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (134 mg, 66%). LCMS (m/e) 301 (M—N(CH2)4SO2); 1H-NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 7.73 (d, 2H, J=8.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 6.92 (s, 1H), 6.81 (d, 1H, J=4.8 Hz), 6.76 (d, 1H, J=4.8 Hz), 3.63 (s, 2H), 3.10-3.03 (m, 4H), 3.03-2.97 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[S:35][C@H:34]([CH2:36][O:37]CC4C=CC(Cl)=CC=4Cl)[C@@H:23]([O:24]CC4C=CC(Cl)=CC=4Cl)[C@@H:12]3[O:13]CC3C=CC(Cl)=CC=3Cl)[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[S:35][C@H:34]([CH2:36][OH:37])[C@@H:23]([OH:24])[C@@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ccc(COC[C@H]2S[C@@H](n3ccc4c(Cl)ncnc43)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@H]2OCc2ccc(Cl)cc2Cl)c(Cl)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: OC[C@H]1S[C@@H](n2ccc3c(Cl)ncnc32)[C@@H](O)[C@@H]1O
Temperature: -78 °C

Procedure:
To a solution of compound 1-6 from Step F (1 eq) in dichloromethane at −78° C. is added boron trichloride (1M in dichloromethane, 10 eq) dropwise. The mixture is stirred at −78° C. then at −30° C. to −20° C. The reaction is quenched by addition of methanol/dichloromethane (1:1) and the resulting mixture stirred at −15° C., then neutralized with aqueous ammonia at 0° C. and stirred at room temperature. The solid is filtered and washed with CH2Cl2/MeOH (1/1). The combined filtrate and washings are evaporated, and the residue is purified by flash chromatography over silica gel using CH2Cl2 and CH2Cl2:MeOH gradient as the eluent to furnish the title compound 1-7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:9]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(OCC)(=O)C.O>[CH:12]1([NH:11][C:9](=[O:10])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=3)=[CH:3][CH:4]=2)=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(C(=Cc2ccc(F)cc2)C(=O)NC2CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2ccc(C(=Cc3ccc(F)cc3)C(=O)NC3CC3)cc2)cc1
Temperature: 37 °C
Yield: 80 %

Procedure:
To a solution of 2-(4-aminophenyl)-N-cyclopropyl-3-(4-fluorophenyl)acrylamide (0.34 g, 1.15 mmol, prepared according to the procedure described in Example 165, step-I) in dichloroethane (25 mL), methyl-4-formylbenzoate (0.185 g, 1.15 mmol) was added under stirring at 37° C. After stirring for 5 minutes, sodium triacetoxy borohydride (0.39 g, 1.85 mmol) was added to reaction mixture followed by acetic acid (0.3 mL). The reaction mixture was stirred for 8 hours at room temperature. Subsequently the reaction mixture was treated with ethyl acetate:water (1:1, 100 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulphate and evaporation afforded the title compound (0.42 g. 80% yield)
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:8][C@H:7]([NH:9]C(=O)OC(C)(C)C)[CH2:6]1)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][C@H:7]1[CH2:8][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(C)(C)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)[C@H]1C[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [trans-3-(2-hydroxypropan-2-yl)cyclobutyl]carbamate (250 mg, 1.09 mmol) and TFA (10 mL) in DCM (10 mL) was stirred at RT for 2 hours. The resulting mixture was then concentrated in vacuo to afford 2-(trans-3-aminocyclobutyl)propan-2-ol which was used in the next step directly.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:16]2[CH2:17][NH:18][CH2:19][CH2:20][S:21][C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl.C(N(CC)CC)C>ClCCl>[C:1]([N:18]1[CH2:17][C:16]2[C:11]([Cl:10])=[CH:12][CH:13]=[CH:14][C:15]=2[S:21][CH2:20][CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cccc2c1CNCCS2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of benzoyl chloride (3.93 g) in dichloromethane (50 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.5 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (2.82 g) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 15 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethanol/water. Yield 5.93 g (m.p. 64°-72° C.).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[C@@H:23]1([NH2:28])[CH2:26][CH2:25][C@@H:24]1[NH2:27]>CS(C)=O>[NH2:27][C@H:24]1[CH2:25][CH2:26][C@H:23]1[NH:28][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: N[C@@H]1CC[C@@H]1N
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CC[C@@H]1N
Temperature: 95 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 130 mg, 0.439 mmol), cis-cyclobutane-1,2-diamine (Frontier Scientific Services, Newark, Del.; 113 mg, 1.316 mmol), and DMSO (4.4 mL) and stirring at 95° C. for 2 h. Purification by reverse phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 70%) provided rac-2-(3-((cis-2-aminocyclobutyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (15 mg, 9.4%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.83-7.88 (1H, m) 7.55-7.61 (1H, m) 7.34 (1H, t, J=1.00 Hz) 7.09 (1H, s) 4.21-4.30 (1H, m) 3.59-3.67 (1H, m) 3.45-3.53 (1H, m) 3.16-3.23 (1H, m) 3.11-3.15 (1H, m) 2.93-3.08 (1H, m) 2.58 (3H, s) 2.34-2.42 (1H, m) 2.19-2.27 (1H, m) 1.56-1.69 (2H, m). m/z (ESI, +ve) 363.2 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][OH:34])=[CH:28][CH:27]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][OH:34])=[CH:28][CH:27]=3)[C:8]3[S:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCC2)C(F)(F)F
Reactant: Nc1ccc(CCO)cc1
Product: OCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCC3)cc1
Yield: 67.3 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.094 g, 0.24 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.033 g, 0.24 mmol) to afford the title compound (0.062 g, 68%) as a white solid. MW=383.89. 1H NMR (DMSO-d6, 500 MHz) δ 8.81 (s, 1H), 8.24-8.15 (m, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.53-7.48 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.5 Hz, 1H), 3.66-3.59 (m, 2H), 3.46-3.40 (m, 2H), 3.35-3.32 (m, 2H), 2.72 (t, J=7.0 Hz, 2H); APCI MS m/z 384 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[S:17])[CH2:3][N:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:5]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=O>>[CH2:10]([O:9][C:8]1[N:4]([CH2:3][C:2]2[S:17][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[N:1]=2)[N:5]=[CH:6][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:11]
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1OCC
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1OCC
Yield: 82.9 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (200 mg, 0.78 mmol) obtained in Example 8b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (0.53 g, 2.0 mmol), the title compound (275 mg, 83%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([N+:28]([O-])=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Zn].[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([NH2:28])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1N
Yield: 31.6 %

Procedure:
Prepared from 4-(4-tert.-butoxycarbonylamino-3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert.-butyl ester (Example E1) (256 mg, 0.61 mmol) by reduction with Zn/NH4Cl according to the general procedure G (method c). Obtained as an orange foam (75 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[C:14]([S@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15].[Na+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])/[CH:7]=[N:20]/[S:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])[CH3:2]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(/C=N/S(=O)C(C)(C)C)ccc1OC
Temperature: 66 °C

Procedure:
In the first step, a reaction flask was charged with 3-ethoxy-4-methoxybenzaldehyde (2.0 g, 11 mmol), (R)-tert-butylsulfinamide (Ellman's auxiliary) (1.5 g, 12.2 mmol, 1.1 equiv) and THF (20 vol) then treated with Ti(OEt)4 (4.6 mL, 22 mmol, 2.0 equiv, ˜20% Ti). The reaction was heated for ˜6 h at 65-67° C. then cooled to 20-25° C. and added to 2% aqueous NaCl (20 vol). The slurry was filtered and the white precipitate (titanium salts) was washed with EtOAc. The organic portion was dried with MgSO4 and concentrated to afford (E)-N-(3-ethoxy-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (Compound E).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[CH:14](N1CCCCC1)=[O:15]>C(OCC)C>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([CH:14]=[O:15])=[CH:7][N:6]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Cl)nc1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
5-Bromo-2-chloropyridine (T-9) (15.0 g) and diethyl ether (450 ml) were put in a reaction vessel and cooled to −50° C. under an atmosphere of nitrogen. n-Butyllithium (1.57 M in n-hexane; 54.6 ml) was added dropwise in the temperature range of −50° C. to −45° C., and the stirring was continued for another 90 minutes. After the reaction vessel had been cooled to −70° C., formylpiperidine (9.70 g) was added dropwise in the temperature range of −70° C. to −65° C., and the stirring was continued for another 60 minutes while the mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (500 ml) and mixed with it. Diethyl ether (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from heptane. The solvent was distilled off and the product was dried, giving 2-chloro-5-formylpyridine (T-10) (7.01 g). The yield based on the compound (T-9) was 68%.
Reaction SMILES: C([O:4][C:5]1[C:6]([C:15]([NH2:17])=O)=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=O)C.S(Cl)(Cl)=O>>[OH:4][C:5]1[C:6]([C:15]#[N:17])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CC(=O)Oc1cc2ccccc2cc1C(N)=O
Solvent: O=S(Cl)Cl
Product: N#Cc1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 66 %

Procedure:
A mixture of 19 (4.96 g, 21.6 mmol) and thionyl chloride (6.32 ml, 86.4 mmol) was heated under reflux for 2 hours. The solution was concentrated in vacuo to dryness. The residue was taken up in water (10 ml), methanol (200 ml) and 1N NaOH solution (75 ml). The solution was stirred at room temperature for 19 hours and concentrated. Chromatography, eluting with 1:1 cyclohexane/ethyl acetate, provided 2.41 g (66%) of 20 as yellow crystals, mp 188°-189° C. (lit. mp 188°-189° C.).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(Br)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 75.8 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in dimethylformamide (10 mL) was added potassium carbonate (307 mg, 2.229 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (248 mg, 1.486 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg of 3-(6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)-2,2-dimethylpropan-1-ol as a solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:16][OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:24][CH3:25])[C@@H:11]([CH2:16][OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Compound 5 (10 g, 30 mmol) dissolved in DMF (100 ml) was added with K2CO3 (1.1 equiv., 4.56 g) and ethyl iodide (1.1 equiv., 3.16 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 10 g of a semisolid. Yield=93%. 1HNMR (DMSO, 200 MHz) δ 1.17 (3H, t, J=7 Hz), 3.40 (2H, q), 3.54 (3H, s), 3.80 (2H, t, J=5.8 Hz), 4.50 (1H, t), 5.00 (1H, bt), 7.28 (1H, dd, J=4 Hz, J′=1 Hz), 7.57 (1H, dd, J=4.2 Hz, J′=1 Hz).
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.[OH-].[Na+]>CO>[CH2:10]([NH:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C(=NOCc1ccccc1)c1ccccc1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: c1ccc(CNOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 25.0 g O-benzylbenzaldoxime in 100 ml of methanol is mixed with 3.0 g of sodium cyanoborohydride and a few mg of methyl orange indicator. Methanolic hydrochloric acid is added to keep the color of the reaction mixture pale pink (pH=3). After stirring at room temperature for 3 hours, 5.0 more grams of sodium cyanoborohydride is added and the reaction mixture (pH=3) is stirred at room temperature for 12 hours. The reaction mixture is alkalified with aqueous sodium hydroxide and then extracted with methylene chloride. The combined organic layer is washed with water, brine, dried (MgSO4) and evaporated to give the crude product. Liquid chromatography affords the title compound as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](I)=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:41]([OH:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>[Cu]I.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncncc2I)CC1
Reactant: OCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2OCc2ccccc2)CC1
Temperature: 110 °C
Yield: 86.4 %

Procedure:
A sealed tube charged with 4-(5-Iodo-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (780 mg, 2.00 mmol), CuI (38 mg, 0.20 mmol), 1,10-phenathroline (72 mg, 0.4 mmol), Cs2CO3 (912 mg, 2.8 mmol), benzyl alcohol (0.62 mL, 6.0 mmol) and toluene (2 mL) was heated at 110° C. for 40 hours. The resulting suspension was cooled to room temperature and filtered through a silica gel pad, eluting with EtOAc. Evaporation of the solvent followed by flash chromatography on silica gel (10:1 hexanes/EtOAc) provided 4-(5-benzyloxypyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.640 g, 86%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 7.99 (s, 1H), 7.39 (m, 5H), 5.08 (s, 2H), 3.73 (m, 4H), 3.48 (m, 4H), 1.47 (s, 9H). LCMS (APCI+) m/z 371 [M+H]+; Rt=2.52 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[C:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CO.[Pd]>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)=C1COC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)OCc1ccccc1)C1COC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
Pd/C (10%, 5.0 g) was added to a solution of methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (10.0 g, 36 mmol) in MeOH (100 mL). The suspension was stirred under hydrogen atmosphere at ambient temperature for 12 h. The catalyst was filtered off and washed with MeOH (100 mL). The filtrate and washings were combined followed by addition of benzyloxycarbonyl N-succinimide (Cbz-OSu; 10.0 g, 40 mmol) and triethylamine (15.2 mL, 108 mmol). The reaction mixture was stirred for 12 h at ambient temperature and then concentrated. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=5:1) to afford methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3-yl)acetate (4.3 g, 41% yield) as a yellow solid.