Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=2)[C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:28])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]4([C:1]#[N:2])[CH2:4][CH2:5]4)[CH:7]=3)[CH:17]=2)=[N:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
A suspension of 3-(1-cyanocyclopropyl)-N-{2-methyl-5-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (8.5 g, 20.5 mmol), calcium chloride (5.55 g, 50 mmol) and reduced iron (14.5 g, 260 mmol) in ethanol (500 mL)/water (50 mL) was stirred with heating at 80° C. for 4 hr. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethanol. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (6.57 g, 83%) as a green amorphous substance. The amorphous substance was used for the next reaction without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1)=[NH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28](=O)[C:29](=[CH:42]N(C)C)[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1.Cl>O.CO>[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28]3[N:2]=[C:3]([NH:5][C:6]4[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=4)[N:4]=[CH:42][C:29]=3[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1
Reactant: COc1cc(NC(=N)N)ccc1C(=O)O
Reactant: COc1cccc(F)c1C1=NCC(=CN(C)C)C(=O)c2ccc(Cl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Temperature: 52.5 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Into a reactor was added 6 (3.81 kg, 15.5 mol), potassium carbonate (4.3 kg, 31.1 mol), 9 (5.27 kg, 14.1 mol) and methanol (63 L). The suspension was warmed to 50 to 55° C. and stirred for a minimum of 24 h until ≧96.0% conversion was obtained by HPLC analysis. Methanol (10 L) and water (37 L) were added while maintaining the temperature between 50 and 55° C. The pH of the mixture was adjusted to 3.0 to 4.0 using 7% w/w HCl (prepared from 7.0 kg of concentrated HCl and 24 L of water) while maintaining the temperature between 50 and 55° C. The suspension was cooled to 20 to 25° C. over a minimum of 1 h and stirred for at least 60 min. The resulting suspension was filtered and washed with water (2×26.3 L) at 50 to 55° C. and methanol (2×10 L) at 20 to 25° C. The wet cake was dried at 45 to 50° C. under vacuum to provide 5.85 kg (80% yield) of Formula (II). 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J=2.4, 8.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.39 (m, 3H), 7.21 (s, 1H), 6.89 (s, 2H), 3.82 (s, 6H); MS (ESI) m/z MS (ESI) m/z 517.2 (M−H+, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][C@H:12]1[CH:24]=[CH:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O-].[Na+].CO>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH:24]=[CH:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ccnc1C=C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-[2-(1-methylimidazol-2-yl)vinyl]pyrrolidine (11.97 g) in methanol (80 ml) was added conc. hydrochloric acid (4.79 ml) at ambient temperature with stirring and the mixture was allowed to stand overnight at the same temperature. To the reaction mixture was added 28% sodium methoxide-methanol solution (11.4 ml) under ice-cooling with stirring and the resulting insoluble material was filtered off. The filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (200 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-[2-(1-methylimidazol-2-yl)vinyl]pyrrolidine (5.47 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:18]1[C:19]([F:35])=[C:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl.O1CCOCC1>CC1C=CC(C)=CC=1.[Pd]>[CH2:27]([O:26][C:25]([NH:24][C:20]1[C:19]([F:35])=[C:18]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:1][CH:2]=2)[CH:23]=[CH:22][CH:21]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: COCCOc1ccc2c(C(CN)c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2F)c2c1[nH]c1cc(OCCOC)ccc12
Temperature: 125 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a light homogeneous, orange solution of benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-fluorophenylcarbamate (3.5215 g, 7.37 mmol) and ethyl 2-oxoacetate (2.92 mL, 14.75 mmol) (50% in toluene) under nitrogen was added 4N HCl/1,4-dioxane (2.212 mL, 8.85 mmol); reaction turned dark burgundy. The reaction was stirred overnight, concentrated in vacuo, dissolved in EtOAc (50 mL) and saturated aqueous NaHCO3 (20 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (1.569 g, 1.474 mmol) in p-xylene (211 mL), and the solution was heated at 125° C. After 3.5 hr, the reaction was cooled to room temperature, filtered through a pad of CELITE®, and the insolubles were rinsed with EtOAc (250 mL). The filtrate was washed with brine (75 mL), and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 220 g column eluting with 5-40% EtOAc/CH2Cl2. Appropriate fractions (20-25% elution) were collected and concentrated in vacuo to give the desired product (0.811 g, 1.381 mmol, 18.7% yield) as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][NH:6][C:7](=[O:20])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](N(OC)C)=[O:15])[N:13]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][NH:6][C:7]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1)=[O:20]
Reactant: CON(C)C(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reaction time: 2 h

Procedure:
1.0 g of 2-(3-(3,4-dichlorobenzyl)ureido)-N-methoxy-N-methylthiazole-4-carboxamide was dissolved in 20 ml dry tetrahydrofuran and cooled to −78 C. 1.10 eq. of 1 N lithium aluminum hydride in tetrahydrofuran was added slowly. The reaction was stirred at 0 C for 2 hours. The reaction was cooled to −78 C again and quenched with 1 N HCl and extracted with EtOAc three times. The organic was combined, dried over sodium sulfate and concentrated. The residue was purified by column chromatography using 0-100% gradient of EtOAc and hexanes to give 1-(3,4-dichlorobenzyl)-3-(4-formylthiazol-2-yl)urea.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH3:41][NH:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>C1COCC1>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][N:42]([CH3:41])[C:4](=[O:5])[CH2:3][S:7](=[O:8])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CNCC(O)CO
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CC(=O)N(C)CC(O)CO)c3ccccc3)c2)c1
Temperature: 75 °C

Procedure:
To the solution of (S)-ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate (3.5 g, 6.3 mmol) in anhydrous THF (50 mL) was added dropwise 3-methylamino-1,2-propanediol (6.77 g) and the resulting reaction solution was heated at 75° C. for 8.5 hours. The reaction was then concentrated under reduced pressure and the yellow oily residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was separated and washed with saturated aqueous NaHCO3 (1×), brine (1×), and dried with sodium sulfate. The upper clear solution was decanted and evaporated, the resulting yellowish foamy residue was subjected to a gradient column chromatography (from EtOAc-Hex 6:1 to MeOH-EtOAc 1:50) yielding the title compound as white foam in amount of 2.56 g (66%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1
Reactant: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)OCC)n2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.2 %

Procedure:
580 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-6-ethynyl-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 38A; contained 35% of the methyl ester) were initially charged in 30 ml of tetrahydrofuran and 5 ml of methanol, and 7.8 ml of 1N aqueous lithium hydroxide solution were added. The resulting reaction mixture was stirred at room temperature for 6 h and then kept at 0° C. for 16 h. The mixture was then acidified with 6 N hydrochloric acid and concentrated. The solid which formed was filtered off, triturated with a little water and filtered off again. Drying under reduced pressure gave 521 mg of the desired product (quantitative yield).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]([P:63](=[O:66])([OH:65])[OH:64])[CH:60]=[CH:61][CH:62]=1>CN(C=O)C.C(N(CC)CC)C>[P:63]([C:59]1[CH:58]=[C:57]([NH:56][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:62]=[CH:61][CH:60]=1)([OH:66])([OH:65])=[O:64]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc(P(=O)(O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)Nc1cccc(P(=O)(O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Glu-OtBu (236 mg, 0.78 mmol), HOAt (127 mg, 0.936 mmol) and HATU (356 mg, 0.936 mmol) were dissolved in 1 ml of DMF, and triethylamine (0.21 ml) was added to the solution. Ten minutes after, the crude product of (3-aminophenyl)phosphonic acid was added and stirred at room temperature overnight. The solvent was distilled off and the mixture was purified in accordance with the purification step A to give the title compound.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[OH-].[Na+].C(O[CH:11]1[NH:14][C:13](=[O:15])[C@H:12]1[C@H:16]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:17])(=O)C>O.CO>[CH2:1]([S:4][C@H:11]1[NH:14][C:13](=[O:15])[C@@H:12]1[C@H:16]([O:18][Si:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:17])[CH:2]=[CH2:3]
Reactant: C=CCS
Reactant: CC(=O)OC1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCS[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.14 ml of allyl mercaptan and 0.4 g of sodium hydroxide in 25 ml of water under an argon atmosphere was added a solution of 2.87 g of 4-acetoxy-3(S)-[1(R)-{dimethyl-{2-methylprop-2-yl}silyloxy}ethyl]azetidin-2-one in 10 ml of methanol. After 30 minutes, the mixture was partitioned between dichloromethane and water. The separated organic layer was washed with water, was dried over magnesium sulphate, evaporated to dryness, and then chromatographed on silica gel. Elution with ethyl acetate/hexane mixtures afforded 1.8 g of the title compound as white crystals.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.[CH2:16](O)[CH3:17]>>[NH2:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CC(=O)Nc1cc(Br)ccc1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 119 g (0.461 mol) of 2-acetylamino-4-bromobenzoic acid and 3 liters of absolute ethanol was cooled to 0° C. and was then saturated with a stream of dry hydrogen chloride gas. The solution was then heated under reflux for 24 hours. Upon cooling to room temperature, the solution was evaporated to about 750 ml and then poured into 2 liters of aqueous saturated sodium bicarbonate. The aqueous phase was extracted three times with 300 ml portions of chloroform. The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to afford 23.8 g (21%) of ethyl 2-amino-4-bromobenzoate as an oil: ir(CHCl3) 3504 cm, 3390, 1685, 1610, 1580 among others; 1H--NMR(CDCl3) 1.3 ppm triplet, 3H, CH2CH3), 4.3 (quartet, 2H, CH2CH3), 5.8 (broad singlet, 2H, NH2), 6.6 [doublet (part of AB pattern), 1H, aromatic H], 6.8 (singlet, 1H, aromatic H), 7.7 [doublet (part of AB pattern), 1H, aromatic H].
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=[O:34])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]([C:7]2[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=2[O:18][CH3:19])[OH:34])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(C(O)C2CCN(Cc3ccccc3)CC2)c1C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
n-Butyllithium (1.6 M, 19.5 mL, 31.2 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (8.00 g, 30.87 mmol) in tetrahydrofuran (80 mL) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 1-benzyl-4-formylpiperidine (6.23 g, 30.65 mmol). The mixture was stirred for 30 minutes at room temperature, then poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to obtain the title compound (6.17 g, yield 52%). This was oily.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9]C.B(I)(I)I.C(Cl)Cl.N>C(O)C>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]23[CH2:23][CH:18]4[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]4)[CH2:21]2)[CH2:15]3)=[O:13])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC
Agent: IB(I)I
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: O=C(Nc1ccc(O)c(O)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.0 of N-(3,4-dimethoxyphenyl)-1-adamantanecarboxamide and 2.5 g. of boron triiodide to the procedure set forth in Example 6B. Chromatograph the residue obtained thereby on a column containing 35 g. of silica gel using as the eluent a methylene chloride:ethanol: conc. ammonia (90:10:4 v/v). Crystallize the product from chloroform to obtain the product of this Example, m.p. 196°-199°C.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1(O)[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)[CH2:9][CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([N:8]1[CH2:18][C:19]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:17][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN(Cc2ccccc2)CC(O)c2ccccc2)CC1
Agent: Br
Product: c1ccc(CN2CC(c3ccccc3)OC3(CCNCC3)C2)cc1
Temperature: 55 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
To tert-butyl 4-[[benzyl-(2-hydroxy-2-phenyl-ethyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (6.2 g, 14.07 mmol) was added HBr (60 mL of 48% w/w,) and the reaction mixture was stirred at 55° C. for 10 hours. The reaction mixture was evaporated in vacuo, basified the aqueous with 50% aq. NaOH to pH13, then extracted with DCM (3×75 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give 4-benzyl-2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane (4.4 g, 97%) as a yellow oil, which was used directly without further purification. ESI-MS m/z calc. 322.2. found 323.7 (M+1)+; Retention time: 1.72 minutes (3 min run).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=1[O:19][CH3:18])#[N:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1I
Temperature: 60 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
Ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (5.60 g, 0.0145 mol) and 2,4-dimethoxybenzylamine (3.51 mL, 0.0234 mol) were combined in tetrahydrofuran (100 mL) and stirred at 60° C. for 3 days. The reaction was concentrated in vacuo, diluted with dichloromethane and hexanes and the resultant precipitate was filtered to yield the title compound (5.56, 81%) as a yellow solid. LCMS: (FA) ES+, 473. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (s, 1H) 7.10 (d, 1H, J=8.57 Hz), 6.60-6.50 (m, 2H), 4.30 (s, 2H), 4.22-4.14 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.26-1.21 (m, 3H).
Reaction SMILES: [OH:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[CH3:9].[CH:10](N)([CH3:12])[CH3:11].C>O.CC(C)=O>[CH:10]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: CC1=NC=CC(=O)C1O
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(O)c(=O)ccn1C(C)C
Reaction time: 0.5 h

Procedure:
1-Isopropyl-3-hydroxy-2-methylpyrid-4-one was prepared by refluxing 3-hydroxy-2-methylpyrid-4-one (Maltol) (10.0 g) with 3 equivalents of isopropylamine (99%) in 200 ml of water for 8 hours. Decolorizing charcoal was added after refluxing and the mixture was stirred for 0.5 hours. The mixture was then filtered through a medium frit filter containing 0.5 inches of Celite. The filtered solution was then concentrated in vacuo (rotary evaporator) to remove the water and excess amine, leaving a dark thick oil. The oil was then dissolved in minimal amounts of hot acetone and filtered (repeatedly) through a medium frit filter. Brownish crystals (product) remained on the frit and these were then washed (3X) with 1 ml portions of hot acetone to obtain white crystals. m.p. 239°-242 ° C.
Reaction SMILES: [OH-].[Na+].C1COCC1.[C:8]([C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=3)[C:32]([O:34]C)=[O:33])=[O:25])[CH2:20][CH2:19]2)[CH:13]=[CH:14][CH:15]=1)#[N:9].Cl>O>[C:8]([C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=3)[C:32]([OH:34])=[O:33])=[O:25])[CH2:20][CH2:19]2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C#N)c3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(CCC2CCN(C(=O)Oc3cncc(C(=O)O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
An aqueous 1 M sodium hydroxide solution (0.69 ml) was added to a THF (5 ml)/water (4 ml) solution of methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (272 mg), followed by stirring overnight at room temperature. 1 M hydrochloric acid (0.69 ml) was added to the reaction liquid, and the crystal precipitated was collected by filtration. The crystal was washed with a hot methanol/water solution, and dried to obtain 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid (240 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([OH:22])=O)=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:22])=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccncc1
Reactant: Cc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1cc2c(cc1C(=O)Nc1ccncc1)SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 87.4 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (1.00 g), 4-aminopyridine (321 mg) and 2-chloro-1-methylpyridinium iodide (949 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (1.08 g) was obtained as a pale-brown amorphous solid.