Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(S(F)(F)[F:24])CC)C.C([O-])(O)=O.[Na+]>ClCCCl>[F:24][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of compound obtained in step II (24.5 g, 0.1 mol) in 1,2-dichloroethane (300 mL) cooled to −10° C. was added diethylaminosulfur trifluoride (19.7 mL, 0.15 mol) over a period of 30 minutes. The reaction mixture was stirred at this temperature for 1 h then at room temperature for 16 h. The reaction mixture was quenched by adding mixture of crushed ice (300 g) and solid NaHCO3 (25.2 g, 0.3 mol). The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 1-tert-butyl 2-methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate as a viscous liquid (24.7 g) in 100% yield. [α]D −53.3, (c, 1.0, CHCl3). m/z (M+1) 248; 1H NMR (CDCl3) 300 MHz δ 5.20 (ddd, J=3.8, 3.8, 49.1 Hz, 1H), 4.55 (d, J=9.5 Hz, ½H), 4.42 (d, J=8.9 Hz, ½H), 3.90-3.55 (m, 2H), 3.75 (s, 3H), 2.55-2.20 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH3:31])=[N:29][CH:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[C:30]([CH3:31])=[N:29][CH:28]=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1ncnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Yield: 24.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (80 mg, 0.119 mmol), DCM (4.0 mL) and TFA (1.0 mL, 13.0 mmol) for 3 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (15 mg, 24%) as a white powder. LCMS: m/z=514.8 (M−1); 1H NMR (400 MHz, D2O) δ 7.86 (s, 1H), 6.89 (s, 1H), 5.36-5.28 (m, 1H), 4.78-4.66 (m, 1H assumed; obscured by solvent residual peak), 4.54-4.44 (m, 1H), 4.42-4.30 (m, 1H), 2.35 (s, 3H), 1.25 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:17])[C:12](=[N+:15]=[N-:16])[CH:13]=O)[CH3:9].O>CCO>[CH2:8]([O:10][C:11]([C:12]1[N:15]=[N:16][N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:17])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)nn1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. Reaction mixture was concentrated to get the residue. Cold water was then added, filtered the solid precipitated to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]2[CH2:33][NH:34][CH2:35][C:28]=12>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:34]2[CH2:33][C:29]3[C:28](=[N:27][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Reactant: c1cnc2c(c1)CNC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(N2Cc3cccnc3C2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (50.0 mg, 0.189 mmol) was dissolved in THF (3 mL) and then DIPEA (0.0990 mL, 0.568 mmol) was added, followed by the addition of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.0270 g, 0.227 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and water (5 mL) was added to the resulting residue. The aqueous solution was extracted with EtOAc (2×25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 12 g, 30% EA/petroleum ether) to afford 2-chloro-5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazine (29.0 mg, 44.0%) as a brown solid. LCMS Condition B-79: retention time 1.70 min, [M+1]=348.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.38 (br s, 2H), 4.84 (br s, 2H), 6.80 (d, J=2.8 Hz, 1H), 7.25 (dd, J=7.7 Hz, J=4.9 Hz, 1H), 7.35-7.54 (m, 5H), 7.64 (br s, 1H), 7.90 (d, J=2.7 Hz, 1H), 8.34 (d, J=4.3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: C=CCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 14 h
Yield: 101.1 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 2.4 g, 60.5 mmol, 1.1 eq) and diethyl malonate (8.34 mL, 55 mmol, 1 eq) in DMF (200 mL) was cooled to 0° C. and 5-bromo-1-pentene (6.5 mL, 55 mmol, 1 eq) was added dropwise. The reaction mixture was warmed to rt, stirred for 14 hours and then partitioned between ether and water. The layers were separated, the aqueous layer was extracted with ether (2×250 mL) and the combined organic phases were washed with water (2×) and brine, dried over MgSO4 and concentrated to give E1.1 as a colorless oil (12.7 g, 100% yield). 1H NMR (400 MHz, CDCl3): δ 5.71 (m, 1H), 4.92 (m, 2H), 4.12 (q, J=7.1 Hz, 4H), 3.25 (t, J=7.58 Hz, 1H), 2.01 (m, 2H), 1.83 (m, 2H), 1.36 (m, 2H), 1.20 (t, J=7.1 Hz, 6H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:23])=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=2)[C:7]([O:13][CH3:14])=[C:8]([CH:10](Cl)[CH3:11])[CH:9]=1.[CH3:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[NH:27][N:26]=1.O>CN(C)C=O>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([CH:10]([C:8]3[C:7]([O:13][CH3:14])=[C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=4)[C:5]([CH3:23])=[C:4]([Cl:3])[CH:9]=3)[CH3:11])[N:26]=[C:25]([CH3:24])[C:33]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred at 30° C. overnight. The mixture was treated with water and then filtered to provide the desired product. LCMS calculated for C22H21ClN7O (M+H)+: m/z=434.1; Found: 434.2
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1.[C:18]([O:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:31][CH:30]=3)=[CH:12]2)=[C:4]([F:17])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Yield: 75.1 %

Procedure:
According to Scheme 19 Step 1: The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 2.81 mmol, 0.89 g, Example 1 Step 2) and 4-(tert-butoxycarbonyl)aminophenylboronic acid (1.5 eq, 4.20 mmol, 1.00 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 2 hours at 80° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 50 g SiO2, CH2Cl2/AcOEt 90/10). The resulting brown solid washed twice with acetonitrile to afford tert-butyl 4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenylcarbamate (2.11 mmol, 0.90 g, 75%) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Li]CCCC.CCCCCC.[CH:25](N1CCOCC1)=[O:26]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:25]=[O:26])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A solution of 4-bromo-1-iodo-2-trifluoromethoxy-benzene (1.00 g, 2.72 mmol) in THF (15 mL) was cooled to −78° C., and 2.66 M BuLi in hexane (2.05 mL, 5.44 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1.5 h, and N-formylmorpholine (0.57 mL, 5.63 mmol) was added. The reaction mixture was stirred at −78° C. for 15 min and at ambient temperature for 80 min. The reaction was quenched with 0.25 M aqueous citric acid (10 mL), and the resulting mixture was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 2% to 5% EtOAc in hexane) to give 4-bromo-2-trifluoromethoxy-benzaldehyde (560 mg, 77%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[N:37]=[C:38]=[O:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8])=[O:39]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2cc(C(F)(F)F)ccc2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.2 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-chloro-2-isocyanato-4-(trifluoromethyl)benzene (60 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (152 mg, 78%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH:11]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1CC=C(c2ccncc2[N+](=O)[O-])CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cnccc1C1=CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-(3-nitropyridin-4-yl)cyclohex-3-enone (1.0 eq) in methanol (0.2 M) was added sodium borohydride (1.8 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was dissolved with ethyl acetate (200 mL), and washed with sat. NaCl (30 mL). The organic was dried with MgSO4, filtered and concentrated to give 4-(3-nitropyridin-4-yl)cyclohex-3-enol (85%). The crude product was used in the next step without further purification. LC/MS (m/z): MH+=221.0, Rt=0.55
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH:21]=[CH:22][CH2:23]Br>CC(C)=O>[Br:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: BrCC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OC/C=C/CBr
Temperature: 55 °C
Yield: 41.1 %

Procedure:
A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 59 mmoles), K2CO3 (10 g, 1.2 q) and 1,4-dibromo-2-butene (>95% trans, Aldrich, 18 g, 1.2 eq) in acetone (500 ml) was heated at 55° C. for 3 hr. At the end of the reaction, the solvent was concentrated. The crude product was extracted into dichloromethane (750 ml) and the insolubles were filtered; then the solution was concentrated again to an oil. Purification on a silica gel column (SiO2, 100 g, eluted with dichloromethane) yielded 7.25 g (40%) of white solid. Recrystallization from ether gave analytically pure (E)-1-[4-[4-(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.91 g), m.p.=71°-72° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1.C(N(S(F)(F)[F:20])CC)C>>[Cl:1][C:2]1[C:7]([C:8]2([F:20])[CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1ccc(C2(O)COC2)c(Cl)n1
Reactant: CCN(CC)S(F)(F)F
Product: Cc1ccc(C2(F)COC2)c(Cl)n1
Yield: 56 %

Procedure:
In analogy to the procedure described in Example 130 b), 3-(2-chloro-6-methylpyridin-3-yl)oxetan-3-ol (Example 134 a, 1.5 g, 7.51 mmol) was reacted with diethylaminosulfur trifluoride to obtain the title compound (850 mg, 56%) as colorless liquid, MS (ESI): m/e=202.1 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]#[C:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].[CH3:17][CH2:18][O:19][C:20](/[C:22](/Cl)=[N:23]\[OH:24])=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:24][N:23]=[C:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])[C:11]=1[C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: CSc1ccc(C#CC(=O)C2CC2)c(Cl)c1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc(-c2ccc(SC)cc2Cl)c1C(=O)C1CC1
Yield: 35.5 %

Procedure:
A mixture of 1-[2-chloro-4-(methylsulphenyl)phenyl]-3-cyclopropylprop-1-yn-3-one (1.39g) and ethyl chloro-oximidoacetate (0.84 g) in toluene was stirred and heated at reflux overnight. It was cooled and evaporated to dryness. The residue was purified by chromatography eluted with a mixture of hexane and dichloromethane, followed by ether to give ethyl 5-[2-chloro-4(methylsulphenyl)phenyl]-4-cyclopropylcarbonylisoxazole-3-carboxylate (compound 9, 0.72g) as an orange solid, m.p. 50° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1)#[CH:2].P(Br)(Br)[Br:12]>C(Cl)Cl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:12])=[CH:5][CH:4]=1)#[CH:2]
Reactant: BrP(Br)Br
Reactant: C#Cc1ccc(CO)cc1
Solvent: ClCCl
Product: C#Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethynylbenzyl alcohol a (1 g, 7.57 mmol) was diluted in 20 ml DCM, and cooled to 0° in ice bath. Phosphorus tribromide (4.1 g, 15 mmol) was added dropwise. The reaction was allowed to warm to room temperature gradually, and stirred under nitrogen overnight. The reaction was quenched by addition of H2O in ice bath, extracted by DCM. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by chromatography (ISCO) using 100% hexane to give pure 4-ethynylbenzyl bromide b (220 mg). M+H+ 195.1
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.[Si:34]([O:41][C@@H:42]([C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76])[C@@H:47]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:49][O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:43][NH:44][CH3:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:44]([CH3:45])[CH2:43][C@@H:42]([O:41][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:76])[CH3:77])[C@@H:47]([O:66][Si:67]([C:70]([CH3:71])([CH3:72])[CH3:73])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:60])[CH3:61])[CH2:49][O:50][Si:51]([C:54]([CH3:55])([CH3:56])[CH3:57])([CH3:53])[CH3:52])=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CNC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of acid 225 (220 mg, 0.474 mmol, scheme 54), amine 242 (309 mg, 0.474 mmol) and DIPEA (0.331 mL, 1.895 mmol) in DMF (5 mL) was added HATU reagent (270 mg, 0.710 mmol). The mixture was stirred overnight at room temperature then partitioned between ethyl acetate and water. The organic layer was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge) to afford title compound 243 (250 mg, 0.254 mmol, 54% yield) as a white solid. MS: 985.4 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13].[CH3:25]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([O:24][CH3:25])([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CI
Reactant: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSC(F)(F)C(Cn1cncn1)(OC)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 60% sodium hydride (0.16 g, 4.0 mmol) in N,N-dimethylformamide (50 ml), 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazole-1-yl)-2-propanol (1.0 g, 3.0 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (0.56 g, 3.9 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[2-(2,4-difluorophenyl)-3-ethylthio-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.81 g, yield: 78%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH2:13]([O:15]C(=O)COC1C([N+]([O-])=O)=NC(Br)=CC=1)C>C(O)(=O)C.CCOC(C)=O.[Fe]>[O:12]=[C:8]1[CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([CH:13]=[O:15])=[N:11][C:10]=2[NH:9]1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 90 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one. To a solution of (6-bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester (3.14 g, 10.3 mmol) in glacial acetic acid (12.4 mL) was added iron powder (1.67 g, 29.9 mmol). The suspension was heated to 90° C. and stirred for 6 h, after which it was cooled to RT and diluted with EtOAc (50 mL). The mixture was filtered through a pad of SiO2 and the filtrate was concentrated. Recrystallization from CH3OH provided 1.32 g (57%) of the title compound as a solid. MS (ESI): exact mass calculated for C7H5BrN2O2, 227.95; m/z found, 228.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.98 (d, J=5.3, 1H), 7.16-7.09 (m, 1H), 6.98 (dd, J=8.0, 4.9, 1H), 4.68 (d, J=1.4, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[SH:11][CH2:12][C:13]([OH:15])=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:15])[CH2:12][S:11][C:9]2=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)CS
Solvent: CCN(CC)CC
Product: O=C1CSC(=S)N1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A mixture of 27 g. (0.16 m.) of p-chlorophenyl isothiocyanate, 33 ml. (42.5 g., 0.475 m.) of mercaptoacetic acid and 5 drops of triethylamine is heated in a pressure bottle at 120°-130°C. for 21/2 hours. The reaction mixture is allowed to stand at room temperature overnight and filtered. The crude product is recrystallized from ethanol to give 3-(4'-chlorophenyl)-rhodanine, m.p. 124.5°-126°C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[CH2:17][NH2:18].[BH4-].[Na+]>CCCCCC>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(OC(C)C)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(Cc1ccc(OC(C)C)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
1-(4-Isopropoxyphenyl)propan-2-one (1.92 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.71 g) were condensed and subsequently reduced with sodium borohydride (2.00 g) by an analogous procedure to that described in Example 1. Chromatography of the crude product on silica gel using 1% methanol-dichloromethane as eluent gave N-[2-(4-isopropoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, mp 58°-61° C. (hexane) as a 42:58 mixture of diastereoisomers.