Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH2:3][CH3:4])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH:1]([NH:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:18]([N:17]([CH3:21])[CH3:16])=[O:19])[CH:9]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CCC(C)NC(=O)Cc1cccc(N)c1
Solvent: c1ccncc1
Product: CCC(C)NC(=O)Cc1cccc(NC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
20.6 g (0.1 mol) of 3-amino-phenylacetic acid sec.-butylamide were dissolved in 100 ml of pyridine. 10.75 g (0.1 mol) of dimethylcarbamic acid chloride were added thereto. The mixture was stirred for a further 2 hours at room temperature and 2 hours at 50° to 60° C. The residue which remained after distilling off the pyridine under reduced pressure was stirred with very dilute hydrochloric acid, filtered off and then recrystallized from butyl acetate. 17 g (61.5% of theory) of 3-(N',N'-dimethylureido)-phenylacetic acid sec.-butylamide of melting point 170-171° C were obtained.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:23])=[C:7]2[C:14]([NH2:15])=[C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:12][C:8]2=[N:9][C:10]=1[CH3:11])(=O)C.[Li+].[OH-]>CO>[NH2:15][C:14]1[C:7]2[C:8](=[N:9][C:10]([CH3:11])=[C:5]([OH:4])[C:6]=2[CH3:23])[S:12][C:13]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(=O)Oc1c(C)nc2sc(C(=O)OC(C)(C)C)c(N)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1O
Reaction time: 8 h
Yield: 702.8 %

Procedure:
To a solution of tert-butyl 5-acetoxy-3-amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate (19.6 g, 5.8 mmol) in methanol (300 mL), was added a 5% solution of aqueous LiOH (150 mL) and the mixture was stirred overnight. The precipitate was collected and washed with water to provide tert-butyl 3-amino-5-hydroxy-4,6-dimethyl-thieno [2,3-b]pyridine-2-carboxylate (12 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[Cl:22])[OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[Cl:22])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(OC)ncc(Cl)c2Cl)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(Cl)c2Cl)c(OC)c1OC
Temperature: 25 °C
Yield: 64.3 %

Procedure:
13.8 g (159 mmol) of manganese dioxide was added to a solution having 4.66 g (12.0 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(4,5-dichloro-2-methoxy-3-pyridyl)methanol obtained in Step (f) dissolved in 30 ml of toluene, followed by reflux with heating for 2 hours. After cooling to room temperature, manganese dioxide was removed by filtration on the pad of celite, and toluene was distilled off under reduced pressure, followed by purification by silica gel column chromatography to obtain 2.98 g (yield: 65%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-4,5-dichloro-2-methoxypyridine.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([CH:7]=O)=[C:4]([CH:9]=O)[CH:3]=1.[C:11]1(=[O:18])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[OH-].[K+]>>[I:1][C:2]1[S:6][C:5]2[CH:7]=[C:15]3[C:14](=[O:17])[C:13]4[C:12](=[CH:9][C:4]5[CH:3]=[C:2]([I:1])[S:6][C:5]=5[CH:7]=4)[C:11](=[O:18])[C:16]3=[CH:9][C:4]=2[CH:3]=1
Reactant: O=Cc1cc(I)sc1C=O
Reactant: O=C1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Product: O=C1c2cc3cc(I)sc3cc2C(=O)c2cc3sc(I)cc3cc21
Temperature: 20 °C
Yield: 86.6 %

Procedure:
5-Iodo-2,3-thiophenedicarboxaldehyde (20.00 g, 75.15 mmol) and 1,4-cyclohexandione (4.25 g, 37.12 mmol) were dissoved in IMS (industrial methylated spirits) (600 cm3) by warming and stirring, and then cooled to 20° C. with a water bath. 5% KOH solution (7.5 cm3) was added in one portion under nitrogen with vigorous stirring. The reaction mixture was stirred at 20° C. for 30 minutes and the precipitate formed was collected by suction filtration, washed with IMS, water, IMS, then acetone, and dried in the vacuum oven at 40° C. overnight to yield 2,8-diiodo-anthra[2,3-b:7,6-b′]dithiophene-5,11-dione (18.39 g, 87%). The solid was directly used for the following reactions without further purification.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([O:8][C@H:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O.[CH2:37]1COCC1.C1(C)C=CC=CC=1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:6]([O:8][C@H:9]2[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:10]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:37])[CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=1
Reactant: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 2.50 g (4.9 mmol) of 2-(R)-(3,5-bis(trifluoro-methyl)benzoyloxy)-3-(S)-phenyl-4-benzyl morpholine from Example 67) and 2.50 g (12.0 mmol) of dimethyl titocene (from Example 68, Step A) in 35 mL of 1:1 v/v THF/toluene was stirred in an oil bath at 80° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150 g of silica gel using 3:1 v/v hexanes/methylene chloride as the eluant afforded 1.71 g (69%) of the title compound as a solid. Alternatively, the product may be isolated by crystallization from methanol, following precipitation of titanium residues. Mass Spectrum (FAB): m/Z 508 (M+H, 25%).
Reaction SMILES: C(OC1C=C(C(NC(C2CCCCCC2)=O)C2C(Cl)=NC=CN=2)C=CC=1)C1C=CC=CC=1.[CH3:33][O:34][C:35]([C@H:37]1[CH2:42][CH2:41][C@@H:40]([C:43](=O)[NH:44][CH:45]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:54]=2)[C:46]2[C:51]([Cl:52])=[N:50][CH:49]=[CH:48][N:47]=2)[CH2:39][CH2:38]1)=[O:36]>>[CH3:33][O:34][C:35]([C@H:37]1[CH2:38][CH2:39][C@@H:40]([C:43]2[N:47]3[CH:48]=[CH:49][N:50]=[C:51]([Cl:52])[C:46]3=[C:45]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH:54]=3)[N:44]=2)[CH2:41][CH2:42]1)=[O:36]
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)NC(c2cccc(OCc3ccccc3)c2)c2nccnc2Cl)CC1
Agent: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCCCCC1
Product: COC(=O)[C@H]1CC[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn32)CC1

Procedure:
cis-4-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester (compound of Formula II-A where Z=cyclohexyl, CO2A3=4-cis-CO2Me, and Q1=Ph-(3-OBn)) was prepared according to the procedures described for 1-(3-benzyloxy-phenyl)-8-chloro-3-cyclobutyl-imidazo[1,5-a]pyrazine (compound of Formula II where R1=cyclobutyl and Q1=Ph-(3-OBn)) above except for the substitution of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]amide (compound of Formula III where R1=cyclobutyl and Q1=Ph-(3-OBn)) with cis-4-{[(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-carbamoyl}-cyclohexanecarboxylic acid methyl ester (compound of Formula III where R1=trans-4-cyclohexane carboxylic acid methyl ester and Q1=Ph-(3-OBn)); MS (ES) 476.2 (M+1), 478.2 (M+3).
Reaction SMILES: [C:1]1([CH3:12])[C:2]([CH3:11])=[CH:3][C:4](S([O-])(=O)=O)=[CH:5][CH:6]=1.[Na+].[NH2-:14].[Na+].N>>[NH2:14][C:4]1[CH:5]=[CH:6][C:1]([CH3:12])=[C:2]([CH3:11])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1C
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Product: Cc1ccc(N)cc1C
Yield: 88.1 %

Procedure:
In a 200-ml autoclave were placed 35 grams (0.163 moles) of anhydrous sodium 4-o-xylene sulfonate, 14 grams (0.35 mole) of sodium amide and 120 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 120° to 125° C for 15 hours. The reaction pressure in the autoclave was 90 to 100 atm. during the reaction. After the ammonia was removed, 15 ml of methanol was added to the reaction mixture for solvolysis. Thereafter 500 ml of water was added to the product and the mixture was treated in the same manner as in Example 1, whereby 17.4 grams of 3,4-xylidine boiling at 112° C/22 mm Hg was obtained. Yield was 88.1%.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13]CS([O-])(=O)=O)(=[O:4])=[O:3].[CH3:19][N:20]1[C:25]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][C:23](=[O:32])[N:22]([CH3:33])[C:21]1=[O:34]>C(Cl)(Cl)Cl>[CH3:19][N:20]1[C:25]([N:26]2[CH2:31][CH2:30][N:29]([CH2:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:28][CH2:27]2)=[CH:24][C:23](=[O:32])[N:22]([CH3:33])[C:21]1=[O:34]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: CS(=O)(=O)Oc1ccccc1CCCS(=O)(=O)[O-]
Solvent: ClC(Cl)Cl
Product: Cn1c(N2CCN(CCc3ccccc3OS(C)(=O)=O)CC2)cc(=O)n(C)c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 163.3 %

Procedure:
A mixture of 1 g of 2-(2-methanesulfonyloxyphenyl)ethylmethane sulfonate and 0.65 g of 1,3-dimethyl-6-(piperazin-1-yl)-2,4(1H,3H)-pyrimidinedione was stirred at 90° C. for 2 hours and then allowed to stand for cooling. The resultant reaction mixture was dissolved in 50 ml of chloroform, and then washed with 10 ml of a 1N aqueous sodium hydroxide solution. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the residue was purified through a silica gel column chromatograph (chloroform/methanol=40/1 in volume ratio), thereby obtaining 2.0 g of 1,3-dimethyl-6-[4-(2-[2-methanesulfonyloxyphenyl]ethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12](C(=O)C)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:20]>Cl.C(OCC)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:20]
Reactant: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1C
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(=O)C2CCNCC2)cc1C

Procedure:
A suspension of 1-(4-(4-methoxy-3-methylbenzoyl)piperidin-1-yl)ethanone (5.45 g, 19.8 mmol) in 6 N HCl (40 mL) was heated to reflux for 12 h then concentrated in vacuo to a light purple solid. The material was taken up in ˜100 mL MeOH with heating and sonication, concentrated in vacuo to ˜25 mL, added diethyl ether (˜200 mL) to form white precipitate and a purple aqueous layer. The aqueous layer was removed via a pipet and concentrated in vacuo. The suspension was decanted through filter to recover a white solid (1.30 g). The aqueous material was concentrated in vacuo to form a purplish oil which was taken up in diethyl ether and the resulting suspension was filtered (0.82 g). The filtrate was concentrated in vacuo to a purple oil. The solid material was confirmed to be the title compound. Calculated molecular formula=C14H19NO2=233.31. found MS (ESI) m/e 233.9 (M+H+)
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[O:7])C>O1CCCC1>[CH3:16][N:12]([CH2:13][CH2:14][CH3:15])[C:11]([C@@H:9]1[CH2:10][C@H:8]1[C:6]([OH:7])=[O:5])=[O:17]
Reactant: CCCN(C)C(=O)[C@@H]1C[C@H]1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)[C@@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 1 N lithium hydroxide (25.6 mL, 25.59 mmol) to a solution of trans-2-(methylpropylcarbamoyl)-cyclopropane carboxylic acid ethyl ester (1.02 g, 5.1194 mmol) in tetrahydrofuran (30 mL). Stir vigorously for 2 days at room temperature. Concentrate and treat with water (50 mL) and extract with diethyl ether (50 mL). Acidify the aqueous layer with 1 N hydrochloric acid (26 mL) and extract with diethyl ether (3×125 mL). Combine the organic extracts, dry (magnesium sulfate) and concentrate to give the title compound as a racemic mixture (0.84 g, 89%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[NH:7]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1>O1CCCC1>[O:3]=[C:2]1[C:15]2=[C:16]3[C:11](=[CH:12][C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[C:1]1=[O:5]
Reactant: CCOC(=O)Cc1ccc2c(c1)CCCN2
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc2c3c(c1)C(=O)C(=O)N3CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the refluxing mixture of oxalyl chloride (0.3 ml) in dry tetrahydrofuran (THF; 15 ml) was added ethyl 1,2,3,4-tetrahydroquinolin-6-ylacetate (500 mg) in dry THF (5 ml) dropwise. The mixture was refluxed for 4 hours after addition was completed, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in carbon disulfide (20 ml) and added aluminum chloride (610 mg) portionwise. The mixture was refluxed for 4 hours and allowed to stand for overnight at room temperature. After decantation of the solvent, ice water (20 ml) was added to the residue. The mixture was extracted with chloroform and dried over anhydrous sodium sulfate. Evaporation of chloroform afforded the title compound. The compound was recrystallized from acetonitrile to give 490 mg (75%) of dark red needles, mp 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[N:6]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:7](=[O:29])[N:8]([CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10](=[O:22])[N:11]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12]3)[C:4]=2[CH:3]=1.[CH:43](=O)[CH3:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[N:6]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C:7](=[O:29])[N:8]([CH:9]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:10]([N:11]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:17][CH2:18][N:19]([CH2:43][CH3:44])[CH2:20][CH2:21]4)[CH2:12]3)=[O:22])[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@H](N4CCNCC4)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CCN1CCN([C@H]2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccc(OC)cc4)c4ccc(Cl)cc43)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 99.0 mg (0.16 mmol) of 5-chloro-1-(4-methoxybenzenesulfonyl)-3-[2-oxo-1-phenyl-2-((S)-3-piperazin-1-yl-pyrrolidin-1-yl)ethyl]-1,3-dihydrobenzimidazol-2-one (example 149) in 4 ml of THF was mixed with 7.15 mg (0.16 mmol) of acetaldehyde and 160 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.41 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (mobile phase: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator). Yield: 38.6 mg (38%) of colorless solid
Reaction SMILES: C([N:8]([CH2:37]C1C=CC=CC=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:36])COS(C)(=O)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])C1C=CC=CC=1.Cl>CO.[Pd]>[C:24]([O:23][C:21]([C@H:20]1[CH2:28][CH:29]([OH:36])[CH2:37][NH:8][C@@H:9]1[C:10]([OH:12])=[O:11])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)[C@@H](CC(O)COS(C)(=O)=O)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1CC(O)CN[C@@H]1C(=O)O

Procedure:
To a solution of 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinate from step 1k (5.02 g, 8.2 mmol) in methanol (40 mL) was added Pd-Black and 1M HCl (4 mL) solution. The mixture was hydrogenated under H2 at 50 psi overnight. The catalyst was filtered off and the solution was concentrated to dryness. The residue was dissolved in ethanol and triethyl amine (2 mL) was added. The solution was refluxed for three hours and then concentrated to dryness to provide the crude compound (2S,3S)-3-(tert-butoxycarbonyl)-5-hydroxypiperidine-2-carboxylic acid, the compound was directly used in the next step. MS (ESI): 189.9 (M+H+−t-Bu); 246.0 (M+H+); 268.0 (M+Na+).
Reaction SMILES: N[C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([I:22])[N:10]=[C:11]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)[N:4]2[N:3]=1.N(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[I:22][C:9]1[N:10]=[C:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]2)[N:4]2[C:5]=1[C:6](=[O:8])[NH:7][CH:2]=[N:3]2
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]c(N)nn32)CC1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl trans-4-(2-amino-5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.880 g, 0.00211 mol) in anhydrous THF (74 mL) and DMF (13.2 mL) was charged with tert-butyl nitrite (1.2 mL, 0.010 mol) and stirred at rt for 2 h. The reaction was concentrated in vacuo and was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 570 mg, (67% yield) of the title compound as a pale orange solid. (1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.54 (m, 2H), 1.56-1.69 (m, 2H), 1.92-2.06 (m, 4H), 2.36-2.46 (m, 1H), 3.02-3.14 (m, 1H), 3.61 (s, 3H), 7.89 (d, J=3.28 Hz, 1 H) and 11.79 (br. s., 1H); MS (ES+): m/z 402.86 [MH+].
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.O[CH:18]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:19]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20]([OH:22])=[O:21].B(F)(F)F>C(Cl)Cl>[CH3:30][C:19]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:18][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(Oc1ccccc1)(C(=O)O)C(O)c1cccs1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Cc1cccs1)(Oc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of triethylsilane (56.4 g, 77.4 mL, 485 mmol) in 100 mL of CH2Cl2 at −20° C., boron trifluoride diethyl etherate (68.8 g, 61.5 mL, 485 mmol) was added. A solution of 3-hydroxy-2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid (45.0 g, 162 mmol) in CH2Cl2 (600 mL) was then added dropwise to the BF3 solution over 1 h, keeping the temperature at −15° C. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with 1 N NaOH (approx. 360 mL) diluted with 180 mL of water and the pH was adjusted to pH=4.0 using 1 N HCl and 1 N NaOH. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×300 mL). The combined organic layers were then washed with 0.1 N HCl (300 mL) and water (2×300 mL). Xylene (150 mL) and NaCl were added and the organics were concentrated to dryness to yield 40.0 g of crude product. The product was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 6.86-7.29 (m, 8H), 3.53 (d, 2H), 3.37 (d, 2H), 1.44 (s, 3H); MS (EI) 263.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[ClH:24]>[Pd].CO>[ClH:24].[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:23])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CCNC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 20 %

Procedure:
This compound was prepared by the catalytic hydrogenation (palladium on carbon) of 8.0 g (0.02 mole) of N-[2-(dimethylamino)ethyl]-4-(4-nitrophenyl)-1-piperazinecarboxamide in 150 ml of methanol for 1 hour. The filtered mixture was concentrated under reduced pressure to give an oil as residue. The oil was converted to the hydrochloride in ethereal hydrogen chloride. The solid was recrystallized from methanol-water to give 2.0 g (20%) of the title compound as a white solid, m.p. 114°-116° C.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][C@H:27]1[O:32][CH2:31][CH2:30][NH:29][C@@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:30][CH2:31][O:32][C@H:27]([CH3:26])[C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: COC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 51.1 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.88 g, 1.9 mmol) was reacted with (2R,3S)-2-methylmorpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34 to give the title compound as a yellow solid (0.51 g, 51%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:27][O:28][C:29](=[O:41])[C:30]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][C:33](Cl)=[N:32][CH:31]=1.C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C)C(=O)C.CCOC(C)=O.O>[CH3:27][O:28][C:29](=[O:41])[C:30]1[C:35]([C:36]([F:37])([F:38])[F:39])=[CH:34][C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:31]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
To a solution of 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile (Example 141, step 5, 100 mg) in N,N-dimethylacetamide (1 ml) were added methyl-6-chloro-4-(trifluoromethyl)-nicotinate (75 mg), triethylamine (34 mg) and 1,4-diazabicyclo[2.2.2]octane (4 mg). The mixture was stirred at room temperature for 6 h and then diluted with EtOAc. Water was added. The mixture was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>2:3) to give the title compound (132 mg) as a colorless solid. MS (m/e, ISP neg. ion)=585.1 [M−H+].