Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[CH2:27][N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=O)[CH:13]2[CH2:12]1)=O>C1COCC1>[OH:8][CH2:9][CH:11]1[CH2:27][N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH:13]2[CH2:12]1
Reactant: COC(=O)C1CC2C(=O)N(Cc3ccccc3)CCN2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CC2CN(Cc3ccccc3)CCN2C1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A suspension of 3.20 g (84.3 mmol) of lithium aluminum hydride in 30 mL of dry THF was cooled to 0° C. and treated dropwise with a solution of 8.00 g (27.7 mmol) of 7-methoxycarbonyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-1-one (Jones, R. C. F., Howard, K. J., J. Chem. Soc., Perkin Trans. 1, 1993, 2391) in 80 mL of dry THF. After 30 min the reaction was carefully quenched with 3 mL of water, 3 mL of 15% NaOH and 9 of mL water. The mixture was filtered, the filtrate evaporated, the residue taken up in ethyl acetate and washed with brine. The organic layer was dried (magnesium sulfate), filtered, and evaporated to give 6.09 g (89%) of the title compound as a mixture of (7RS,8aSR)- and (7SR,8aSR)-isomers of sufficient purity for use in the next reaction (Preparation 2). m/z (MH+) 247.
Reaction SMILES: [C:1]1([C:7]2([NH2:16])[CH2:15][CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30]([NH:16][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:31]
Reactant: NC1(c2ccccc2)CCC2CCCN2C1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC2CCCN2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 55 mg (0.254 mmol) 6-phenyl-octahydro-indolizin-6-ylamine (example A.3) and 130 ul (0.762 mmol) N-ethyldiisopropylamine in dichloromethane (0.9 ml) was added drop-wise a solution of 63 mg (0.22 mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (example B.1) in dichloromethane (0.6 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. The solution was washed once with a 2M sodium carbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 50%) to provide 26 mg (y: 22%) of example 3 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 1, first running compound) as a light yellow gum, MS (m/e): 465.2 (M+H+) and 49 mg (y: 41.5%) of example 4 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 2, second running compound) as a white solid, MS (m/e): 465.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([CH:22]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)#[N:2].[Br:24]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:23][Br:24])=[C:7]([CH:22]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1OCCNC(=O)c1ccc(C#N)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)NCCOc2cc(C#N)ccc2CBr)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
12.0 g (39.3 mmol) of N-[2-(5-cyano-2-methylphenoxy)ethyl]-4-cyanobenzamide was dissolved in 200 ml of carbon tetrachloride. 7.00 g (39.3 mmol) of N-bromosuccinimide and 700 mg (4.26 mmol) of azoisobutyronitrile were added to the solution. After stirring at 100° C. for 3 days, 16.8 g (94.4 mmol) of N-bromosuccinimide and 2.1 g (12.8 mmol) of azoisobutyronitrile were added to the resultant mixture, and they were stirred for additional 2 days. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([N:21]2[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:25]1[N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: O=C(Cl)c1ccnn1-c1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccnn1-c1ccccc1
Yield: 62.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0454 g, 0.192 mmol), 1-phenyl-1H-pyrazole-5-carbonyl chloride (0.041 g; 0.192 mmol), and triethylamine (0.068 mL; 0.481 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 4 to 30% of ethyl acetate in dichloromethane gave 0.044 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-phenyl-1H-pyrazole-5-carboxamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:15][CH:16]=O.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:15]=[CH:16][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccn2ccnc2c1

Procedure:
To a solution of 4-chloro-pyridin-2-ylamine (25.0 g, 0.194 mol) in EtOH (250 ml) was added NaHCO3 (32.7 g, 0.389 mol) followed by a 50% solution of chloroacetaldehyde in water (37 mL, 0.292 mol). The mixture was refluxed for 6 h. The solvents were removed under reduced pressure and the crude mixture was diluted with water (250 ml) and extracted with EtOAc (2×125 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure to give 7-chloro-imidazo[1,2-a]pyridine (32.7 g). 1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d), 7.64 (2H, d), 7.56 (1H, s), 6.79 (1H, dd).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:3][CH:2]=1.O>C(OCC)C>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH:7]([OH:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:5][CH:6]=1
Reactant: C=CCCCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: C=CCCCC(O)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
1-Biphenyl-4-yl-hex-5-en-1-one (1 g) was dissolved in diethyl ether (25 ml) NaBH4 (2.5 g) was added and the mixture stirred for 30 minutes. Water (50 ml) was added and most of the solvent evaporated under vacuo. The residue was poured into water and the product extracted with ethyl acetate. The organic layer was dried (Na2SO4) and the ethyl acetate evaporated under vacuum to give a white solid. δC (CDCl3, 62.9 MHz): 25.2, 33.6, 38.5, 74.3, 114.8, 126.4, 127.1, 127.2, 128.8, 138.6, 140.5, 140.9 and 143.9.
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([N:12](COC)[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=2)(=[O:14])=[O:15])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1Br)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of N-[2-(2-Bromo-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.167 mmol) in 3 ml of 4M HCl in dioxane and 1 mL of water was refluxed for 3 hours. After cooling to rt the mixture was concentrated, diluted with water and then sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (30% ethyl acetate in hexane) to afford 50 mg of title compound as an off white solid. MS: (M+H)/z =555.3, (M+Na)/z=575.3.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=O)[CH2:12][CH2:11]1.B(F)(F)F.CCOCC.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:16]1[C:15]2[C:13]3=[N:4][C:3]4[C:2]([C:1]([NH2:9])=[C:12]3[CH2:11][CH2:10][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=4
Reactant: O=C1CCCCc2ccccc21
Reactant: N#Cc1ccccc1N
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Nc1c2c(nc3ccccc13)-c1ccccc1CCC2
Yield: 86.1 %

Procedure:
To a solution of anthranilonitrile (0.69 g, 5.8 mmol) and 1-benzosuberone (1.03 g, 0.96 mL, 6.4 mmol) in 25 mL anhydrous toluene was added boron trifluoride etherate (0.91 g, 0.81 mL, 6.4 mmol) slowly via syringe under a nitrogen atmosphere. The reaction was heated to reflux for 22 h. After cooling, sodium hydroxide solution (25 mL, 2 M, 50 mmol) was added. The reaction was heated to reflux for 23 h. After cooling, the reaction was diluted with ethyl acetate, washed with water (3×50 mL), brine (20 mL), dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue (1.46 g) was dissolved in ethyl acetate:diethyl ether (1:1; 100 mL) with a trace of methanol (3 mL). To the solution was added 7 mL of a 1 N solution of HCl in diethyl ether. A resulting precipitate was collected by vacuum filtration and air-dried to provide the hydrochloride salt of the title compound as an off-white solid (1.30 g, 75%). MS (API+): M+1: 261 (100%); 1H NMR (300 MHz, DMSO-d6/TFA-d) d 2.13-2.29 (br m, 2H), 2.51-2.56 (br m, 2H), 2.56-2.75 (br m, 2H), 7.49 (d, J=7.0 Hz, 1H), 7.55-7.65 (m, 2H), 7.67-7.74 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.91-7.98 (m, 1H), 8.05 (d,J=8.7 Hz, 1H), 8.57 (d, J=8.7 Hz, 1H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)C2)=NC=1CC.[CH2:33]([O:35][C@H:36]1[CH2:40][NH:39][CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[CH3:58])=[C:44]([CH2:59][CH3:60])[N:43]=1)[CH3:34]>>[CH2:33]([O:35][C@H:36]1[CH2:40][N:39]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[CH3:58])=[C:44]([CH2:59][CH3:60])[N:43]=1)[CH3:34]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.31, 2.13, 2.47, 2.71, 3.45˜3.59, 3.77, 3.85, 4.03, 4.28, 4.93, 5.21, 6.54, 6.81, 6.83, 7.11, 7.26; IR (diffuse reflectance) 2970, 2932, 2403 (w), 2350 (w), 2334 (w), 2212 (w), 1965 (w), 1608, 1537 (s), 1482 (s), 1393, 1294, 1242, 1200, 1165 cm−1 HRMS (ESI) calcd for C25H33N5O2S+H1 468.2433. found 468.2416.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]=[C:11]=[O:12].[N-:13]=C=O.[NH2:16][C:17]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](N)[CH:24]=2)[CH2:21][N:20]=[C:19]2[O:30][CH:31]=[CH:32][C:18]=12>>[NH2:16][C:17]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([N:10]([C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[F:1])[C:11]([NH2:13])=[O:12])=[CH:25][CH:24]=2)[CH2:21][N:20]=[C:19]2[O:30][CH:31]=[CH:32][C:18]=12
Reactant: COc1ccc(F)c(N=C=O)c1
Reactant: [N-]=C=O
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Product: COc1ccc(F)c(N(C(N)=O)c2ccc(N3CN=c4occc4=C3N)cc2)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using 2-fluoro-5-methoxyphenyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 394 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]([OH:25])=O)=[CH:14]1.Cl.[C:27]1([C:33]2([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:41]3[CH:37]([CH2:38][NH:39][CH2:40]3)[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[C:51]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]3[CH:37]([CH2:38][N:39]([C:23](=[O:25])[CH2:22][C:15]4[C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[NH:13][CH:14]=4)[CH2:40]3)[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])([OH:42])[CH2:35][CH2:34]2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
0.41 g of carbonyldiimidazole is added to a solution of 0.44 g of 3-indolylacetic acid in 20 cm3 of dry methylene chloride. The mixture is stirred at room temperature for 1 hour and a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry methylene chloride and then 0.7 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of methylene chloride, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (35/65 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in diisopropyl ether. 0.17 g of (3aRS,4RS,7aRS)-7,7-diphenyl-2-(3-indolylacetyl)-4-(2-methoxyphenyl)-perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[CH3:31][C:32]([CH3:34])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH:32]([CH3:34])[CH3:31])[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: CC(C)=O
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(C)C)C1
Product: Cl
Yield: 107.1 %

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (1.0 g, 2.26 mmol) and acetone (250 μL, 3.39 mmol) in dry 1,2-dichloroethane. Add sodium triacetoxyborohydride (1.0 g, 4.53 mmol) and stir overnight at room temperature. Add 1 N NaOH solution to the reaction mixture and extract with CH2Cl2 (2×25 mL). Combine the organic portions and wash with water (2×25 mL). Dry the organic layer with Na2SO4, then filter, and concentrate in vacuo. Triturate the crude yellow solid with Et2O and filter. Wash the solid with Et2O several times and re-dissolve in CHCl3. Add 1 N HCl/Et2O solution (1.5 mL) and remove the solvent in vacuo to give 630 mg (53%) of the title compound. ES/MS m/z (35Cl) 484.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:36](O)=[O:37]>>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:8]=1)[CH:36]=[O:37]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1c(C)c(Cc2ccc(O)cc2)c(OC)c(OC)c1OC
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)phenol (14.5 g, 45.60 mmol) and hexamethylenetetramine (8.30 g, 59.29 mmol) were dissolved in trifluoroacetic acid (100 ml) followed by heating at 80° C. with stirring for 4 hours. After completion of the reaction, the solvent was evaporated therefrom, water (100 ml) was added to the resulting residue and the mixture was stirred for 30 minutes and extracted with methylene chloride. The extract was washed with water and dried, the solvent was evaporated therefrom and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (12.20 g, 35.26 mmol, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([Cl:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:40](Cl)(=O)[O:41]C1C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[Cl:32][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[NH:15][C:16]([C:18]1[C:19](=[O:31])[N:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:21]([CH3:24])[C:22]=1[CH3:23])=[O:17])[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:41])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CCOCC4)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (125 mg, 0.28 mmol) and Et3N (0.12 mL, 0.84 mmol) in THF (4.0 mL) was added phenyl carbonochloridate (0.10 mL, 0.84 mmol). The mixture was stirred at rt for 2 hours, then morpholine (0.15 mL, 1.68 mmol) was added. The resulted mixture was stirred rt for 22 hours, then partitioned between aqueous NH4Cl solution (20 mL) and DCM (20 mL). The organic phase was separated and the aqueous phase was extracted with DCM (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=20/1), followed by washing with methanol (4 mL) to give the title compound as a beige solid (60 mg, 38%).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[C:6]2[CH:7]=[C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:20]=[S:2]1(=[O:1])[C:6]2[CH:7]=[C:8]([NH:11][C:12]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:19])[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 31.7 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (1,1-dioxido-1-benzothien-6-yl)carbamate (263 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.811 mmol) and diisopropylethylamine (0.129 ml, 0.811 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 106 mg (31.7%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:32](Cl)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:32]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 56 mg, 0.36 mmol), 2,6-lutidine (54 μL, 0.49 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride (˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then diluted with methylene chloride (10 mL) transferred to a separatory funnel and the layers separated. The aqueous layer was then extracted methylene chloride (3×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 55% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 90 mg, 55%) as a white foam: ES-HRMS m/e calcd for C22H28N3O4SClF2 (M+H)+ 504.1530, observed 504.1526; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.68-2.33 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.90 (m, 1H, ArCHCO), 4.66 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.52 (d, J=2.2 Hz, 1H, Ar), 7.60 (d, Jo=8.3 Hz, 1 H, Ar), 7.71 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).