Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:34]=[C:35]1[NH:39][CH:38]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>ClCCl.CN(C)C1C=CN=CC=1>[O:43]=[C:42]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH2:8][S:9][CH3:10])[CH2:41][CH2:40][CH:38]1[CH2:37][CH2:36][C:35](=[O:34])[NH:39]1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)CCC1CCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.025 mol) L-methionine methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.42 ml (0.028 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes, filtered, and a mixture of the following is added in a single addition: 6.32 g (0.03 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 3.85 g (0.025 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 19:1 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields crystalline analytically pure N-[1-oxo- 3-(5-oxo-2-pyrrolidinyl)propyl]-L-methionine, methyl ester with a melting point of 98°-100° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.ClC(OC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:32]=[N+:33]=[N-:34])=[O:16])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Agent: COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CCCCc1cnc(-c2ccc(C(=O)N=[N+]=[N-])cc2)nc1
Temperature: -4 °C
Reaction time: 1.25 h

Procedure:
A suspension of 12.62 g of p-(5-butyl-2-pyrimidinyl)benzoic acid in 150 ml of acetone was treated dropwise with a solution of 8.1 ml of triethylamine in 25 ml of acetone while cooling with an ice/sodium chloride bath (internal temperature -4° C.) and thereafter dropwise within 15 minutes with a solution of 4.9 ml of methyl chloroformate in 25 ml of acetone. The suspension was stirred for a further 75 minutes and then treated dropwise within 10 minutes with a solution of 4.90 g of sodium azide in 17.5 ml of water. The mixture was stirred for another 1 hour while cooling with the ice/sodium chloride bath and then for 30 minutes without cooling. The mixture was poured on to 300 ml of ice-water and extracted once with 250 ml of diethyl ether and twice with 100 ml of diethyl ether each time. The extracts were washed with 100 ml of water, dried and concentrated in vacuo at a bath temperature of 35° C., whereby 13.32 g of solid, yellowish p-(5-butyl-2-pyrimidinyl)benzoic acid azide were obtained. The azide was dissolved in 100 ml of toluene and the solution was added dropwise slowly to a flask heated to 90° C., whereby a strong evolution of nitrogen took place. The solution was heated to 108° C. for a further 1.5 hours and then concentrated. There were obtained 11.59 g of crude, pale yellow p-(5-butyl-2-pyrimidinyl)phenyl isocyanate; m.p. 48° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=[O:19])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:34])=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18]([Cl:34])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)Cl)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3β-acetoxy-5-cholenic acid (50.0 g, 118 mmole) in dry dichloromethane (200 ml) was added dropwise oxalyl chloride (30 ml, 448 mmole). The solution was stirred at room temperature for one hour and then concentrated in vacuo to obtain 3β-acetoxy-5-cholenic acid chloride 331. 1H NMR (400 MHz, CDCl3) δ: 0.70 (3H, s, 18--CH3), 0.95 (3H, d, 21--CH3), 1.05 (3H, s, 19--CH3), 2.04 (3H, s, --OCOCH3), 4.60 (1H, m, 3α-H), 5.38 (1H, m, 6-H). Compound 331 was used in the following step without purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of methyl 4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}benzoate (Preparation 3, 3.2 g, 9.6 mmol, 1 eq) in dioxane (20 ml) was added a 2M solution of lithium hydroxide (20 ml) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with water, washed with ethyl acetate and then acidified with concentrated HCl. The resulting precipitate was collected by filtration to yield the title compound as a light brown solid (3.0 g, 9.0 mmol, 98%).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38].Cl>CC#N.CCOC(C)=O>[CH:1]1([CH:7]2[CH2:12][N:11]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])(=[O:39])=[O:38])[CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNCC1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccccc2F)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To a solution of 3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (15.0 mg, 0.036 mmol, 1.0 equiv) in MeCN (0.2 mL) at room temperature, was added NaOH (0.40 mL, 1.5 N solution, 0.60 mmol, 16.7 equiv) and 2-fluoro-benzenesulfonyl chloride (11.4 mg, 0.059 mmol, 1.64 equiv). The mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 3 N HCl (0.3 mL), and then diluted with EtOAc (10 mL). The mixture was washed with water (5 mL), brine (5 mL), then dried (over Na2SO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (0.1% NH4OH) to give product (5.0 mg, 24%) as white solid. MS: 543 [M−H+]. 1H-NMR (400 MHZ, CDCl3): δ 1.12 (m, 3H), 1.34 (m, 1H), 1.45-1.90 (m, 7H), 2.70-2.87 (m, 2H), 3.34 (d, 1H), 3.60-3.70 (m, 2H), 3.95 (d, 1H), 4.18 (d, 1H), 7.13 (s, 1H), 7.21 (t, 1H), 7.27 (t, 1H), 7.30-7.40 (m, 3H), 7.51-7.61 (m, 3H), 7.83 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:5][N:6]=[C:7]=[S:8].[CH:13]([NH:15][NH2:16])=[O:14]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:5][NH:6][C:7](=[S:8])[NH:16][NH:15][CH:13]=[O:14]
Reactant: NNC=O
Reactant: Fc1cc(F)cc(CN=C=S)c1
Solvent: CCO
Product: O=CNNC(=S)NCc1cc(F)cc(F)c1
Yield: 56 %

Procedure:
3,5-Difluorobenzyl isothiocyanate (9.9 g, 25.5 mmole) and formyl hydrazine (1.7 g, 28.7 mole) were refluxed in ethanol (30 ml) for one hour. The reaction was evaporated to dryness, triturated with hexane:ethyl acetate (1:1), filtered, and recrystallized from ethanol-hexane to yield 3.5 g (35%) of crude 4-(3',5'-difluorobenzyl)-1-formyl-3-thiosemicarbazide.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCO
Agent: O=C1c2ccccc2C(=O)C1(O)O
Product: O=C(NCCCO)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl trifluoroacetate (14.1 g; 0.1 mol) was added dropwise to 3-amino-1-propanol (6 g; 0.08 mol) cooled to 0° C. The mixture was stirred at 0° C. for 60 min; the completion of the reaction was confirmed by a negative Ninhydrin test. Volatiles were removed by rotary evaporation and the residue purified by vacuum distillation to provide N-(3-hydroxypropyl)trifluoroacetamide as a clear, viscous liquid in a yield of 13.4 g (98%). 1H-NMR (500 MHz, CDCl3): δ=3.52-3.57 ppm (m, 2H), 2.17 ppm (bs, 1H), 3.54 ppm (dt, J=6.0, 6.0 Hz, 2H), 3.81 ppm (t, J=5.5 Hz, 2H), 7.28 ppm (bs, 1H), 13C-NMR (500 MHz, CDCl3): δ=30.42, 38.35, 61.05, 115.93 ppm (q, J=1142 Hz), 157.76 ppm (q, J=150 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[CH2:10][C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[CH2:10][C:9]2=[S:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1CC(=O)N(c2ccc(F)cc2)C(=O)C1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CC(=O)N(c2ccc(F)cc2)C(=S)C1
Temperature: 100 °C
Reaction time: 30 h
Yield: 57.5 %

Procedure:
A mixture of 1.02 g (4.68 mmol) of N-(4'-fluorophenyl)-3-methylglutarimide (Compound 66), 0.88 g (2.2 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (known as Lawson's Reagent), and 6 ml of hexamethylphosphoramide in a 50 ml round-bottomed flask was warmed to 95°-100° C. for 21 hours. An additional 1.05 g (2.5 mmol) of Lawson's Reagent were added and heating to 100° C. was continued for an additional 30 hours. The mixture was allowed to cool to room temperature and water (50 ml) was added. The mixture was extracted with ether (4×50 ml). The organic portions were combined, dried over MgSO4 and the solvent was removed in vacuo. The resulting 2 g of orange oil were purified via flash chromatography (silica gel, 1:1 hexanes/methylene chloride) to yield 300 mg (28% yield) of yellow oil which solidified to a solid: m.p. 84.5°-87.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH3:10][N:11](C=O)C.[Cu]C#N>N1C=CC=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:10]#[N:11]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: N#C[Cu]
Solvent: c1ccncc1
Product: N#Cc1cc(F)cc(Br)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3-dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (2×30 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (3×40 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chromatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35%). 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1 H), 7.54-7.50 (m, 1 H), 7.35-7.32 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15]2>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18]([CH2:17][C:16]3[C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=4[NH:9][C:15]=32)=[CH:19][CH:20]=1
Reactant: Cc1cc(C)cc(NN)c1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c2c3c([nH]c2c1)-c1cc(F)ccc1C3
Temperature: 85 °C

Procedure:
To a solution of 3,5-dimethylphenylhydrazine (2.54 g, 14.7 mmol) and 5-fluoro-1-indanone (2.21 g, 14.7 mmol) in ethanol (24 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Ethanol was removed in vacuo and the resulting orange solid was dissolved in isopropanol (24 mL). Sulfuric acid (36N, 1.65 mL) was added via syringe and the mixture was stirred at reflux (90° C.) for 17 hours and subsequently cooled to room temperature. The solution was basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of a precipitate. The solid was collected by vacuum filtration to yield 47b in 76% crude yield (2.80 g, 11.2 mmol). Crude product was brought on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.32-7.35 (dd, 1H, J=8.2, 5.2 Hz), 0.24-7.26 (m, 1H), 7.01-7.05 (m, 2H), 6.79 (s, 1H), 3.83 (s, 2H), 2.60 (s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.7 (d, J=361.5), 150.0 (d, J=12.0 Hz), 140.9, 140.6, 131.8, 131.2, 128.9, 122.6, 122.3, 121.6 (d, J=4.5 Hz), 117.2 (d, J=13.5 Hz), 113.4 (d, J=25.5 Hz), 113.1 (d, J=25.5 Hz), 109.6, 31.7 (d, J=3.0 Hz), 21.8, 19.3; 19F NMR (CD3CD, 376 MHz): δ −117.9 (m).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)[N:11]=1>>[ClH:9].[ClH:9].[N:19]1([C:12]2[N:11]=[C:10]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]3)[N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][NH:16]3)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Clc1nc(-n2ccc3ccccc32)c2nc[nH]c2n1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(-n3ccc4ccccc43)c3nc[nH]c3n2)CC1
Temperature: 140 °C

Procedure:
1.31 g of trans-1,4-diaminocyclohexane are brought to its melting temperature (70° C.), 310 mg of product obtained in stage 1 above are added, and the mixture is then heated at 140° C. for approximately 18 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with an MeOH—NH4OH: 98-2 mixture for eluent. 4 ml of ethanol and then 2 ml of hydrochloric acid-ethanol (8N) are added. Partial drying followed by washing with ethanol are carried out. Drying is carried out under vacuum. 23 mg of expected product are obtained, in the form of beige-colored crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:19]=O)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH2:19][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C=O)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
Compound 92 (1.58 g, 5.37 mmol) and morpholine (0.64 mL, 10.7 mmol) were dissolved in 1,2-dichloroethane (26 mL), and sodium triacetoxyborohydride (3.41 g, 16.1 mmol) was added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=30:1) to afford the entitled Compound 93 (1.15 g, 57%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.[OH:22][C:23]1[C:24]([CH3:38])=[C:25]([CH3:37])[C:26]2[O:30][CH:29]([CH2:31][CH2:32][CH2:33]O)[S:28][C:27]=2[C:35]=1[CH3:36].O.CN(C)[CH:42]=[O:43]>C1C=CC=CC=1.C1CCCCC1>[CH:42]([O:22][C:23]1[C:24]([CH3:38])=[C:25]([CH3:37])[C:26]2[O:30][CH:29]([CH2:31][CH2:32][CH2:33][I:20])[S:28][C:27]=2[C:35]=1[CH3:36])=[O:43]
Reactant: II
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Reactant: CN(C)C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: Cc1c(C)c2c(c(C)c1OC=O)SC(CCCI)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g of triphenylphosphine and 1.5 g of iodine were dissolved in 5 ml of dimethylformamide, and the solution was stirred for 30 minutes at room temperature, after which 0.5 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71) was added, and the reaction mixture was allowed to react for 20 hours at room temperature. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate, and the benzene was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography and the final reaction products were fractionated using a 1:2 by volume mixture of cyclohexane and benzene. The desired 5-formyloxy-2-(3-iodopropyl)-4,6,7-trimethyl-1,3-benzoxathiole, melting at 91°-93° C., was obtained from the fraction first eluted. Mass spectrum (m/e): 392 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][N:14]2[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:53]([O:55][CH2:56][CH2:57][O:58][NH2:59])=[CH2:54].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:53]([O:55][CH2:56][CH2:57][O:58][NH:59][C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:23])=[O:24])[N:13]=[CH:12]2)=[O:21])=[CH2:54]
Reactant: C=COCCON
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid (0.58 g, 1.05 mmol) in DMF (10 mL) was added EDCI (0.22 g, 1.1 mmol) followed by HOBt (0.16 g, 1.1 mmol) and the reaction mixture stirred at room temperature for 10 minutes. O-(2-vinyloxy-ethyl)-hydroxylamine (0.12 g, 1.1 mmol) and DIPEA (0.2 mL, 1.1 mmol) were added and the reaction stirred for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with an aqueous saturated sodium bicarbonate solution (10 mL) before the aqueous fraction was extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a pale brown solid (439 mg, 66%). LCMS (Method B): RT=4.40 min, [M+H]+=637.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20]>ClCCl>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20]
Reactant: CC(C)(C)OC(=O)CNC(=O)OCCCNc1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)OCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid is added to a solution of 0.6 g of tert-butyl [3-(pyridin-2-ylamino)propoxycarbonylamino]acetate in 10 ml of dichloromethane. After the mixture has been stirred at room temperature for 1 hour, the solvent is distilled off, and the product is co-distilled with toluene, giving the free acid [3-(pyridin-2-ylamino)propoxycarbonylamino]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH2:24])=[O:13])[S:10][C:3]=12
Reactant: N
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc2nccc(Cl)c2s1
Reaction time: 3 h

Procedure:
A 250 mL flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (3.00 g, 13.7 mmol) and CH2Cl2(100 ml) under nitrogen. DMF (cat) (0.100 ml) and oxalyl dichloride (1.49 ml, 17.1 mmol) were added dropwise, and the reaction mixture was stirred for 3 hours, and concentrated in vacuo. The brown solid was redissolved in CH2Cl2(100 ml) and ammonia (gas) (0.233 g, 13.7 mmol) was gently bubbled through the reaction mixture for 5 minutes. The flask was then capped and stirred at room temperature overnight under closed atmosphere. The brown suspension was concentrated in vacuo and the resulting solid was taken up in water (to dissolve the starting material), then collected by filtration to give 7-chlorothieno[3,2-b]pyridine-2-carboxamide. MS m/z=213 [M+H]+. Calc'd for C8H5ClN25OS: 212.66.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=C(C#N)[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-:26].[K+].Cl.C[C:30]([CH3:32])=[O:31]>C(OCC)C>[ClH:1].[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:32]([C:30]([OH:26])=[O:31])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: CC(C)=O
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reaction time: 5 h

Procedure:
10-[(2RS)-1-(1-Pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile hydrochloride (3.72 g) is added to a solution of potassium hydroxide (1.7 g) in glycol (20 cc), and the mixture is stirred for 5 hours under reflux. After cooling, the yellow solution obtained is treated with a 3N solution (10 cc) of ethereal hydrogen chloride and diluted with acetone (100 cc) and ethyl ether (100 cc), then filtered. After seeding, the yellow filtrate allows the crystallization of a product which is drained, washed with ethyl ether (2×10 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (3.5 g) is thereby obtained in the form of yellow crystals, m.p. 215°-217° C.