Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([CH:14]([OH:17])[CH:15]=[CH2:16])=[CH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14](=[O:17])[CH:15]=[CH2:16])=[CH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: C=CC(O)C(=C)c1ccc(OC)c(OCC)c1
Agent: O=[Mn]=O
Product: C=CC(=O)C(=C)c1ccc(OC)c(OCC)c1
Yield: 58.8 %

Procedure:
According to the General Procedure B, MnO2 (1.63 g, 18.70 mmol) and 2-(3-ethoxy-4-methoxyphenyl)-1,4-pentadien-3-ol (200 mg, 0.85 mmol) are converted to give after workup and chromatography (SiO2, PE/EE=2:1, Rf=0.40) the title compound (110 mg, 0.50 mmol) as a yellow oil; C14H16O3 (232.27).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:22]([OH:23])[OH:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OB(O)c1ccccc1OC(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A solution of 2-bromo-trifluoromethoxybenzene (1.0 g, 4.15 mmol) in dry tetrahydrofuran (20 mL) was cooled to −70° C. A 2.5 M solution of n-butyllithium in hexanes (2.0 mL, 4.98 mmol) was slowly added over a 5 min period, keeping the temperature below −65° C. After stirring at −70° C. for 30 min, triisopropylborate (1.5 mL, 6.22 mmol) was added over a 5 min period. After stirring at −70° C. for 30 min, the solution was stirred at room temperature overnight. An aqueous solution of 2N HCl (10 mL) was added and the mixture stirred for 2 hr. The solution was diluted with ethyl acetate (100 mL). The layers were separated and the organic layer successively washed with 2N HCl (2×25 mL), water (1×25 mL), and saturated salt solution (1×25 mL). The solution was dried over anhydrous magnesium sulfate, filtered and concentrated by rotoevaporation to a pale crystalline solid which was triturated with a little hexanes and filtered. The filtrate was concentrated to a white solid. The two solids were combined to yield 434 mg of the title compound which was used without further purification in the subsequent reaction.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:3][C:2]([CH3:5])([CH3:4])[CH2:1][O:6][Si:8]([CH3:11])([CH3:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(C)(C)CO[Si](C)(C)C

Procedure:
1 mole of neopentyl alcohol and 1.5 moles of trimethylchlorosilane together with 0.0005 moles of tetra-n-butyl ammonium bromide were heated under reflux (54°-100° C.) until the IR spectrum did not show an OH band. The product was worked up by fractional distillation at normal pressure.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH:19]([CH2:23][CH3:24])[C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-phenylglycinol (2.00 g, 14.6 mmol) and triethylamine (2.03 mL, 14.6 mmol) in CH2Cl2 (100 mL) at 0° C. was slowly added 2-chlorobutyryl chloride (1.66 mL, 14.6 mmol). After 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with CH2Cl2 (2×75 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-70:30 to 0:100, to give the title compound. MS: m/z=242 (M+1).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH3:6][NH:7][CH:8]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: Cc1noc(C(Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(Cc1ccc2ccccc2c1)c1nc(C)no1

Procedure:
N-methyl-N-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphtyl)ethyl]carbamic acid tertbutyl ester (3.3 g, 9.0 mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (75 ml). After 3 h at 20° C. the reaction mixture was filtered to give 1.52 g of (R) N-methyl-N-{1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}amine hydrochloride.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[N:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH:10]=O)[CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([C:30]23[CH2:35][CH:34]2[CH2:33][NH:32][CH2:31]3)[CH:27]=[CH:28][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O.C([O-])(O)=O.[Na+]>[I:1][C:2]1[C:3](=[O:21])[N:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][N:32]2[CH2:33][CH:34]3[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:37])[F:36])[CH:25]=4)([CH2:35]3)[CH2:31]2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(C23CNCC2C3)c1
Reactant: O=CCCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2CC3CC3(c3cccc(C(F)(F)F)c3)C2)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
To a solution of 3-[5-iodo-2,4-dioxo-3-(phenylcarbonyl)-3,4-dihydro-1(2H)-pyrimidinyl]propanal (P38, 350 mg, 0.88 mmol) and (1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (racemate, reference procedure for preparation reported in WO2005/080382, 200 mg, 0.88 mmol) in dry DCE (10 ml), AcOH was added and the reaction mixture cooled to 0° C. Sodiumtriacetoxyborohydride (224 mg, 1.055 mmol) was added and the reaction left at 0° C. for 4 hrs. Reaction monitored by LC/MS. The mixture was diluted with a saturated solution of NaHCO3 and extracted with DCM. The solvent was evaporated and the crude purified by silica SPE column (20 g) eluting with acetone/toluene 20:80. After evaporation, 250 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(Cl)([Cl:20])(=O)=O>C(OCC)C>[Cl:20][CH:10]([C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1ccccc1OC
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1OC
Yield: 94.8 %

Procedure:
Using ethyl 3-(2-methoxyphenyl)-3-oxopropanoate (1.7 g, 7.4 mmol), sulfuryl chloride (1.2 g, 8.9 mmol) and diethyl ether (100 mL) as starting materials and in the same manner as in Example 20(i), the title compound (1.8 g, 97%) was obtained as colorless oil.
Reaction SMILES: [C:1]([CH:8]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:37][CH3:38])=[CH:12][C:11]=1[CH2:39][CH2:40][CH3:41])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:8]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:37][CH3:38])=[CH:12][C:11]=1[CH2:39][CH2:40][CH3:41])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OCc4ccccc4)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OCc4ccccc4)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
To a solution of the product of Step A (9 mg, 0.014 mmol) CH2Cl2 (1 mL) was added TFA (0.4 mL) at rt dropwise. The solution was stirred at rt for 2.5 hours. After evaporation of the solvent the crude mixture was purified by flash chromatography eluted with CHCl3 /MeOH/NH4OH (80:15:1), to give 3.8 mg of the title compound as a white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[C:15]([CH3:21])[N:14]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:12][C:13]1[N:20]2[C:16]([S:17][C:18]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19]2)=[C:15]([CH3:21])[N:14]=1
Reactant: Cc1nc(C)n2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(C)nc(C)c2s1
Temperature: -30 °C
Reaction time: 1.33 h

Procedure:
To 50 ml of anhydrous THF cooled to −65° C. under the atmosphere of argon was added 10.9 ml of a 1.63 N n-butyl lithium/n-hexane solution, and a solution of 2.564 g of 5,7-dimethylimidazo[5,1-b]thiazole in 17 ml of anhydrous THF was further added dropwise at −64-−60° C. over a period of 15 minutes. The reaction mixture was then stirred at the same temperature for 80 minutes. After 5.0 ml of tri-n-butylstannyl chloride was added dropwise to the mixture at a temperature of −63-−58° C. over a period of 10 minutes, it was warmed to −30° C., and further stirred for 110 minutes. The reaction mixture was diluted with 100 ml of semi-saturated aqueous saline, extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The oil thus obtained was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1-−1:2) to give the title compound as a light orange oil in a yield of 6.164 g.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1C=CC=CC=1)[C:11]1C=CC=CC=1>N1C=CC=CC=1.CCOC(C)=O>[OH:1][CH2:2][C:3]([CH2:8][O:9][Si:10]([CH3:17])([CH3:11])[C:23]([CH3:26])([CH3:25])[CH3:24])([CH2:6][OH:7])[CH2:4][OH:5]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(CO)(CO)CO
Yield: 133.4 %

Procedure:
Pentaerythritol [2,2-bis(hydroxymethyl)propane-1,3-diol] (10.55 g, 77 mmol) was taken up in 100 mL of dry pyridine. Tert-butyldiphenylsilyl chloride (4.26 g, 15 mmol, 0.2 eq) was then added dropwise over 10 minutes to the pyridine solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours at which point TLC (EtOAc) indicated that the reaction was complete. The reaction was worked-up by diluting the reaction mixture with 250 mL of EtOAc and washing the organic layer with 10% HCl (3×200 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo to afford a thick pale yellow oil. Column chromatography on 200 g of silica gel eluting with EtOAc followed by concentration of the appropriate fractions afforded 5.01 g of the product as a clear colorless oil which solidified very slowly upon standing (86%). 1H NMR (CDCl3, 300 MHz): δ1.08 (s, 9H), 3.66 (s, 2H), 3.74 (s, 6H), 7.42 (m, 6H), 7.65 (m, 4H); MS (70 eV, EI) 392 (M+NH4)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:19]([O-])=O)[C:8]([O:17][CH3:18])=[C:9]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:19][C:7]1[C:8]([O:17][CH3:18])=[C:9]([CH:11]([OH:16])[C:12]([F:14])([F:15])[F:13])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: COc1c(C(O)C(F)(F)F)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Yield: 100.1 %

Procedure:
To a solution of 1-(5-tert-butyl-2-methoxy-3-nitrophenyl)-2,2,2-trifluoroethanol (0.440 g, 1.43 mmol) in ethanol (4.7 mL) and water (2.3 mL), ammonium chloride (0.230 g, 4.30 mmol) and iron powder (0.240 g, 4.30 mmol) were added, and the resulting mixture was heated to reflux for 15 hours. The temperature of the reaction solution was returned to room temperature, the insoluble materials were filtered through a Celite pad. After evaporating the organic solvent under reduced pressure, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to obtain 0.397 g of the crude product containing the captioned compound.
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:10][CH2:9][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCC1COC(c2ccc(Br)cc2)OC1
Temperature: 25 °C

Procedure:
A mixture of compound from Example 6 (31 g, 0.21 mol), 4-bromobenzaldehyde (38.8 g, 0.21 mol) and 4-toluenesulphonic acid (110 mg) in dry toluene (200 cm3) was heated under reflux (3 h) using a Dean and Stark apparatus. On cooling to room temperature the mixture was poured into aqueous sodium hydrogen carbonate solution (5%, 70 cm3) and the separated organic layer washed with aqueous sodium hydrogen carbonate solution (5%, 2×60 cm3), water (2×60 cm3) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by crystalliation from methanol to remove the cis-isomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[C:3]([CH3:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(C)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(C)c3)CC2)c(C)c1
Yield: 13.4 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-3-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (388 mg) described in Preparation Example 68 and oxazolidin-2-one (87 mg), the title compound (52.7 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:13]1>>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:12][CH:13]=2)(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1csc2ccccc12
Reactant: COc1nc(N)nc(OC)n1
Product: COc1nc(NC(=O)NS(=O)(=O)c2csc3ccccc23)nc(OC)n1
Yield: 85.7 %

Procedure:
Using the procedure of Example 3, and substituting 1.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine and 2.4 g of benzothiophene-3-sulfonyl isocyanate, a yield of 3.4 g of the desired product was obtained melting at 152°. It showed absorption peaks by Nuclear Magnetic Resonance (60 MC) at; 3.95 δ (CH3O), 7-8 δ (benzohydrogens) and 8.3 δ (thiophene hydrogen) consistent for the desired compound.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[Cl:20][C:21]1[C:27]([O:28][C:29]2[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][C:24]([NH2:25])=[C:23]([F:41])[CH:22]=1>C(OCC)(=O)C>[Cl:20][C:21]1[C:27]([O:28][C:29]2[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][C:24]([N:25]=[C:2]=[O:4])=[C:23]([F:41])[CH:22]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(N)c(F)cc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)COc1ncccc1Oc1cc(N=C=O)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Into a solution of 227 mg of triphosgene in 8 ml of ethyl acetate, a solution of 155 mg of triethylamine and 250 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline in 8 ml of ethyl acetate was added at 0° C. The mixture was stirred for 30 minutes at the same temperature, then for 2 hours at reflux temperature. The reaction solution was filterated while it was hot, and the solvent was distilled off under reduced pressure to obtain 266 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl isocyanate.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][O:36][CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (153 μl, 1.1 mmol) was added followed by methoxyacetic acid (31 μl, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) and the product was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.C(N(CC)CC)C.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34](Cl)=[O:35]>C(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH2:1])=[N:3][C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:34]([CH:30]4[O:29][CH2:33][CH2:32][CH2:31]4)=[O:35])[CH2:18][CH2:17]3)=[N:5][C:6]2=[CH:7][C:8]=1[O:14][CH3:15]
Reactant: O=C(Cl)C1CCCO1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: -5 °C
Reaction time: 2 h
Yield: 154.9 %

Procedure:
37.6 g 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline and 15.8 g triethylamine are suspended in 400 ml methylene chloride. The suspension is cooled to -5° C. This suspension is stirred while 21.0 g tetrahydrofuran-2-carboxylic acid chloride are added drop by drop. The suspension is continued to be stirred for two hours at 0° C., thereafter the solvent is distilled off under vacuum. 200 ml methanol and 200 ml acetone are added to the residue. The resulting suspension is kept under reflux for 0.5 hours while stirring. Thereafter, it is cooled to 0° C. The product is isolated by filtration. 78 g of moist terazosin base are obtained.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C(OC(=O)[NH:18][C:19](=[NH:57])[C:20]1[S:21][C:22]([S:55][CH3:56])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][NH:46][S:47]([C:50]([F:53])([F:52])[F:51])(=[O:49])=[O:48])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:19]([C:20]1[S:21][C:22]([S:55][CH3:56])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][NH:46][S:47]([C:50]([F:52])([F:53])[F:51])(=[O:48])=[O:49])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)(=[NH:18])[NH2:57]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCNS(=O)(=O)C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCNS(=O)(=O)C(F)(F)F)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [2 mL] was added to (imino-{5-methylsulfanyl-4-[6′-methyl-2′-(4-trifluoromethanesulfonylaminobutyrylamino)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (0.020 g, 0.027 mmol) [example 212, step c] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.009 g, 54%) as a solid. 1H-NMR (MeOD): δ 8.29 (s, 1H), 8.03 (md, 1H, J=8.4 Hz), 7.87 (m, 1H), 7.68 (t, 1H, J=7.6 Hz), 7.53 (md, 1H, J=7.6 Hz), 7.34 (t, 1H, J=7.6 Hz), 7.28 (d, 1H, J=7.2 Hz), 7.19 (d, 1H, J=7.2 Hz), 2.98 (m, 2H), 2.72 (s, 3H), 2.06 (s, 3H), 2.05 (t, 2H, J=7.6 Hz), 1.48 (m, 2H). ESI-MS (m/z): Calcd. for C24H25F3N4O5S4: 634.07; found: 635.1.
Reaction SMILES: [NH:1]([C:8](=[O:29])[CH:9]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][N:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[NH:1]([C:8](=[O:29])[CH:9]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of methyl 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinate (66 mg, TFA salt, 0.13 mmol) in MeOH (10 mL) was added a solution of LiOH (35 mg, 1.5 mmol) in water (2 mL). The reaction mixture was stirred at room temperature for 22 h, partially concentrated, neutralized with 1 M aqueous HCl (1.5 mL), concentrated, and dried under high vacuum. 6-[2-Anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinic acid was used without further purification: ESIMS calcd 376.1 (M++H), found 376.1 (M++H).