Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)CC(F)F.[Cl:9][C:10]([Cl:18])([Cl:17])[C:11](Cl)([Cl:15])[CH:12]([Cl:14])[Cl:13]>>[Cl:9][C:10]([Cl:18])([Cl:17])[C:11]([Cl:15])=[C:12]([Cl:14])[Cl:13]
Reactant: ClC(Cl)C(Cl)(Cl)C(Cl)(Cl)Cl
Agent: FC(F)CC(F)(F)F
Product: ClC(Cl)=C(Cl)C(Cl)(Cl)Cl

Procedure:
A method of producing 1,1,1,3,3-pentafluoropropane which comprises reacting 1,1,1,2,2,3,3-heptachloropropane with an alkali metal hydroxide in the presence of a phase transfer catalyst to form 1,1,1,2,3,3-hexachloropropene; continuously reacting, at a constant pressure and in the liquid phase, 1,1,1,2,3,3-hexachloropropene with excess hydrogen fluoride in the presence of at least one of an antimony trihalogenide and an antimony pentahologenide while selectively removing 1,1,1,3,3-pentafluoro-2,3-dichloropropane as it is formed; and reacting gaseous 1,1,1,3,3-pentafluoro-2,3-dichloropropane with hydrogen in the presence of a noble metal catalyst.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:23]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:24]3)[N:9]=[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[C:3]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:23]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:25]([CH2:35][OH:36])[CH2:24]3)[N:9]=[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[C:3]=12
Reactant: COc1cc(C#Cc2nn([C@H]3C[C@@H](CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C#Cc2nn([C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Reaction time: 8 h

Procedure:
(2S,4S)-tert-butyl 4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-((tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate (25 mg) obtained in Step 4 above was dissolved in THF (1.0 ml). Silica gel-supported tetrabutylammonium fluoride (upto 1.5 mmol/g, 34 mg) was added thereto, followed by stirring overnight. Silica gel-supported tetrabutylammonium fluoride (upto 1.5 mmol/g, 30 mg) was further added thereto, and the mixture was further stirred for 2 days. After filtering the reagent off, the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (62 mg). Physical properties: m/z [M+H]+ 495.1
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (6.48 g, 21.78 mmol) in tetrahydrofuran (200 mL) at 0° C. under a nitrogen atmosphere was treated with tert-butyl 4-hydroxy-1-piperidinecarboxylate (13.147 g, 65.33 mmol) and triphenylphosphine (11.43 g, 43.56 mmol) and stirred for 30 minutes. Diethylazodicarboxyate (7.61 g, 43.56 mmol) was added drop-wise over 15 minutes to the reaction solution. The ice bath was removed after 15 minutes, and the reaction mixture was allowed to stir over night. The solvent was evaporated under reduced pressure, and then the yellow gummy solid dissolved in dichloromethane. The solid precipitated was filtered and discarded. The filtrate was evaporated under reduced pressure. Recrystallization from ethyl acetate/heptane yielded 4.82 g (47%) of tert-butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate. 1H NMR (DMSO-d6, 400 MHz) 8.64(s, 1H), 8.20 (s, 1H), 4.89-4.84(m, 1H), 4.13-4.10 (m, 2H), 3.00-2.80(br s, 2H), 2.01-1.88 (m, 4H), 1.43(s, 9H). Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 m, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.825 minutes.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].Cl.[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]([O:3][CH3:4])[C:7]([C:6]([N:2]([CH3:1])[O:3][CH3:4])=[O:10])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A mixture of 48.0 g (0.49 mol) of N,O-dimethylhydroxylamine.HCl in 250 mL of 3:2 v/v CH2Cl2/pyridine was cooled to −78° C. and was treated with 17.4 mL (0.2 mol) of oxalyl chloride maintaining the internal temperature at less than −70° C. The resulting mixture was allowed to warm to rt and stirred for 20 h. The reaction was quenched with 250 mL of sat'd NaCl and the quenched mixture was extracted with 3×400 mL of CH2Cl2. The extracts were combined, dried over MgSO4 and concentrated. Recrystallization from 250 mL of MTBE afforded 24.28 g (69%) of the title compound: 1H NMR (500 MHz) δ 3.25 (s, 6H), 3.75 (s, 6H).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]([CH3:15])([CH3:14])[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>CCOC(C)=O.[Pd]>[F:1][CH:2]([F:16])[C:3]([CH3:15])([CH3:14])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C(=O)OCc1ccccc1)C(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)C(F)F
Yield: 99.6 %

Procedure:
A stirred suspension of benzyl 3,3-difluoro-2,2-dimethylpropanoate (340 mg, 1.49 mmol) and 10% Pd—C (42 mg, 0.04 mmol) in EtOAc (20 mL) was hydrogenated under balloon pressure overnight. The suspension was filtered and the filtrate was evaporated to dryness to afford Cap-11 as a white solid (205 mg). 1H NMR (400 MHz, chloroform-d) δ 6.01 (t, J=1.0 Hz, 1H), 2.07 (br. s, 1H), 1.34 (t, J=1.0 Hz, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(-c2cccs2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a −78° C. solution of 2-(4-methoxyphenyl)thiophene (0.501 g, 2.64 mmol) in anh. CH2Cl2 (40 mL) was added a solution of BBr3 (1M in CH2Cl2, 6.6 mL, 6.6 mmol), keeping the temperature below −60° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture cooled to 0° C. and treated with a saturated NaHCO3 solution. After separation the aqueous layer was extracted with CH2Cl2 and EtOAc. The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (20% EtOAc/hex) to give 4-(2-thienyl)phenol: TLC (20% EtOAc/hex) Rf 0.29.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8]([O:10][C:11](=[O:19])[CH2:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16])[CH3:9].[CH:20]1([C:23]2[C:32]([CH:33]=O)=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21]1>C(O)(=O)C>[CH2:8]([O:10][C:11](=[O:19])[CH2:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])/[CH:16]=[CH:33]/[C:32]1[C:23]([CH:20]2[CH2:21][CH2:22]2)=[N:24][C:25]2[C:30]([C:31]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:9]
Reactant: CCOC(=O)CC(=O)CC(C)=O
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
In a mixture solution of 1.37 g of an oily 60% sodium hydride and 10 ml of tetrahydrofuran, a mixture solution of 2.36 g of 3,5-dioxohexanoic acid ethyl ester and 10 ml of tetrahydrofuran was dropped in 5 minutes while keeping an inner temperature of 20° C. After stirring the mixture for 1 hour at that temperature, a mixture of 2.01 g of 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and 20 ml of tetrahydrofuran was dropped for 20 minutes. After stirring the mixture for 4 hours, a reaction solution was added in 3.09 g of acetic acid and 20 ml of water to terminate the reaction. An organic phase was extracted with 40 ml of ethyl acetate and was then washed with 20 ml of saturated brine, followed by being dried with 2 g of anhydrous sodium sulfate. As a result of analysis on the resulting organic phase, 2.52 g of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dioxohept-6-enic acid ethyl ester (DOXE) (yield 82%) was obtained.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCCN1CCOCC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 4-(2-aminoethyl)morpholine similar to as described in Example 2 to afford 13.3 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(2-morpholinoethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 486 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.02 (d, J=10.5 Hz, 1H), 5.47 (s, 1H), 5.08-4.77 (m, 2H), 4.61-4.48 (m, 2H), 3.70-3.51 (m, 3H), 3.51-3.35 (m, 1H), 2.49-2.30 (m, 3H), 1.49 (s, 6H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:21][C:22]([N:24]1[C:30]2[CH:31]=[C:32]([O:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[C:28](=[O:45])[N:27]2[CH2:46][CH2:47][CH2:48][CH:26]2[CH:25]1[OH:49])=[O:23])[CH:19]=[CH2:20]>CCOC(C)=O>[CH2:18]([O:21][C:22]([N:24]1[C:30]2[CH:31]=[C:32]([O:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[C:28](=[O:45])[N:27]2[CH2:46][CH2:47][CH2:48][C@H:26]2[CH:25]1[O:49][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)=[O:23])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)OC)c(OC)cc2C(=O)N2CCCC2C1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1c2cc(OCCCC(=O)OC)c(OC)cc2C(=O)N2CCC[C@H]2C1OC1CCCCO1
Reaction time: 2 h

Procedure:
Dihydropyran (4.22 mL, 46.2 mmol) was dissolved in EtOAc (30 mL). This solution was stirred 10 minutes in the presence of para-toluenesulphonic acid (catalytic quantity, 20 mg). 17 (2.0 g, 4.62 mmol) was then added in one portion to this solution and allowed to stir for 2 hours. The solution was diluted with EtOAc (70 mL) and washed with saturated aqueous NaHCO3 (50 mL) followed by brine (50 mL). The organic layer was dried (MgSO4), and the solvent removed under vacuum. The oily residue was dried under vacuum to remove any remaining DHP. It was proved pure by TLC (EtOAc) and 18, was retrieved in quantitative yield, 2.38 g (100%). It was used directly in the next step. 1H NMR (CDCl3) as a mixture of 4/5 of diastereoisomers: δ 7.24-7.21 (2H, s×2), 6.88-6.60 (2H, s×2), 5.89-5.73 (4H, m), 5.15-5.04 (6H, m), 4.96-4.81 (2H, m), 4.68-4.35 (4H, m), 4.12-3.98 (4H, m), 3.98-3.83 (8H, m), 3.74-3.63 (8H, m), 3.60-3.40 (8H, m), 2.56-2.50 (4H, m), 2.23-1.93 (12H, m), 1.92-1.68 (10H, m), 1.66-1.48 (20H, m); 13C NMR (CDCl3) δ 173.4, 167.2, 149.1, 132.0, 114.5, 100.0, 98.4, 94.6, 91.7, 68.0, 67.7, 66.3, 63.9, 63.6, 63.3, 62.9, 56.1, 51.6, 51.5, 46.3, 46.3, 31.1, 30.9, 30.7, 30.4, 30.2, 29.0, 25.4, 25.3, 25.2, 24.2, 20.0, 19.8, 19.7; MS (ES+) m/z (relative intensity) 533.2 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Cl:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[N:32]([CH2:34][CH2:35][C:36](O)=[O:37])[CH:31]=[CH:30]2.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[N:32]([CH2:34][CH2:35][C:36]([N:7]1[CH2:6][CH2:5][N:4]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][N:19]=4)(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH2:3][C@H:2]1[CH3:1])=[O:37])[CH:31]=[CH:30]2
Reactant: O=C(O)CCn1ccc2cccc(Cl)c21
Reactant: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CCN1C(=O)CCn1ccc2cccc(Cl)c21

Procedure:
Synthesized according to general procedure 9, method A. The reaction was set up with 0.1 mmol (R)-4-(3-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide, 0.15 mmol 3-(7-chloro-1H-indol-1-yl)propanoic acid, 0.15 mmol BOP reagent, 0.15 mmol triethylamine and DMF (300 μL). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=539.5; tR=2.89 min.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:16]([CH2:47][C:48]([NH2:51])([CH3:50])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].CCN(CC)CC.[C:60](Cl)(=[O:62])[CH3:61]>C(Cl)Cl.O>[CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][C@@H:16]([CH2:47][C:48]([NH:51][C:60](=[O:62])[CH3:61])([CH3:49])[CH3:50])[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)N)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)NC(C)=O)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 1 h

Procedure:
To a solution of 1.0 mmol of 2-[(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1,1-dimethyl-ethylamine, 3.0 mmol of Et3N in 10 ml of CH2Cl2 are added 1.5 mmol of acetyl chloride at 0° C. and the resulting mixture is stirred for 1 h. The reaction mixture is diluted with water and extracted with CH2Cl2. The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf value.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:12]([CH2:15][C:16](=[O:34])[C@@H:17]([NH:26]C(=O)OC(C)(C)C)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:14])=[O:13]>C(OCC)C.ClCCl>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:26][C@@H:17]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](=[O:34])[CH2:15][N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)C[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H](CCc1ccccc1)C(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 70 h
Yield: 97.9 %

Procedure:
A solution comprised of anhydrous p-toluenesulfonic acid (26 mmol) in ethyl ether (10 mL) was added to a suspension comprised of tert-butyl (S)-3-nitro-2-oxo-1-phenethylpropylcarbamate (4.5 g, 14 mmol) in dichloromethane (20 mL) and ethyl ether (150 mL). The mixture was stirred for 70 hours at room temperature and the filtered. The solid collected was washed thoroughly with ethyl ether and dried in vacuo to provide (S)-3-amino-1-nitro-5-phenylpentan-2-one p-toluenesulfonic acid salt (5.4 g, 13.7 mmol) as a white solid. 1H NMR (270 MHz, DMSO-d6): δ 1.92-2.05 (m, 1H), δ 2.15-2.28 (m, 1H), δ 2.29 (s, 3H), δ 2.56-2.76 (m, 2H), δ 4.44 (br.s, 1H), δ 6.97 (d, J=16.1 Hz, 1H), δ 6.29 (d J=16.1 Hz, 1H), δ 7.12 (d, J=8.4 Hz, 2H), δ 7.20-7.35 (m, 5H), δ 7.49 (d, J=8.2 Hz, 1H), δ 8.46 (br.s, 3 NH).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24](O)=[O:25])=[C:7]([CH3:19])[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55]>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:25])=[C:7]([CH3:19])[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)O)c3)c3ccc(Cl)c(F)c32)cn1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)NS(C)(=O)=O)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[6-Chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl]-benzoic acid (0.107 g, 0.245 mmol) in THF (2 mL) at room temperature was added CDI (0.10 g, 0.61 mmol) and DMAP (0.005 g). The resulting mixture was stirred for 18 hrs, after which time DBU (0.15 mL, 0.98 mmol) and methane sulfonamide (0.07 g, 0.74 mmol) were added. The resulting mixture was stirred for and additional 18 hrs at room temperature, then subjected to standard aqueous workup. The crude residue was purified on silica gel (0-10% MeOH in DCM) to afford the title compound.
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (120 mg, 0.26 mmol), 3-methyltetrahydro-4H-pyran-4-one (75 mg, 0.66 mmol), triethylamine (0.15 mL, 1.0 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (0.17 g, 0.79 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (ethyl acetate to EtOAc/Et3N=10:0.1) to yield the desired product (100 mg, 79%). LCMS calculated for C25H38F3N4O2: (M+1) 483.2; found 483.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[N:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[C:20]=[O:21]>ClCCl>[C:15]([O:14][C:12]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([NH:11][C:20]([NH:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)=[O:21])=[CH:7][CH:6]=2)[C:2]([NH2:1])=[N:3]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Reactant: COc1cccc(CN=C=O)c1
Solvent: ClCCl
Product: COc1cccc(CNC(=O)Nc2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)c1
Yield: 69.2 %

Procedure:
1.1 3.3 g of tert-butyl 3,5-diaminoindazole-1-carboxylate (13.3 mmol) and 2.0 g of 1-isocyanatomethyl-3-methoxybenzene (12.3 mmol) are stirred at RT for 24 hours in 40 ml of dichloromethane. The reaction mixture is washed with water, the organic phase is separated off, dried and evaporated. Purification of the residue by column chromatography (eluent ethyl acetate) gives 3.5 g of tert-butyl-3-amino-5-[3-(3-methoxybenzyl)ureido]indazole-1-carboxylate (64%); MS-FAB (M+H+)=412.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 4-methyl-2-nitro-phenylamine (202 mg, 1.33 mmol) and benzaldehyde (0.68 mL, 6.65 mmol) in 5 mL dry dichloromethane at room temperature, was added sodium triacetoxyborohydride (282 mg, 1.33 mmol). Then acetic acid (76 μl, 1.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography to yield 300 mg (1.24 mmol, 94%) of benzyl-(4-methyl-2-nitro-phenyl)-amine.
Reaction SMILES: S([CH:5]1[C@H:9](O)[C@@H:8]([CH2:11][OH:12])[O:7][C@@:6]1(S(C)(=O)=O)[N:13]1[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]1=[O:15])(C)(=O)=O.[OH-].[Na+].[C@@H](N)(C(O)=O)[C@@H](F)C(N)=O.CC(C)([O-])C.[K+]>CS(C)=O.O>[CH3:20][C:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[N:13]([C@@H:6]2[O:7][C@H:8]([CH2:11][OH:12])[CH:9]=[CH:5]2)[CH:21]=1
Reactant: Cc1cn([C@]2(S(C)(=O)=O)O[C@H](CO)[C@@H](O)C2S(C)(=O)=O)c(=O)[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: NC(=O)[C@H](F)[C@H](N)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 79 %

Procedure:
In this synthesis, dimesylthymidine 1 was first treated with sodium hydroxide (3 equivalents) in refluxing water for 2 hours and after work-up the resultant 3,5-anhydrothymidine was treated with potassium t-butoxide in dimethylsulfoxide (DMSO) at room temperature for 2 hours. The reaction mixture was neutralized, evaporated to dryness and after a series of manipulations which included extraction, decolourization, precipitation and recrystallization, gave Stavudine in 79% yield and an overall yield of 56%.