Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]([C:20](=[O:40])[CH2:21][CH2:22][C:23](=[O:39])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42]1.C(ON(CCOCCOCCOC)C(=O)CCC(O)=O)C1C=CC=CC=1>N1C=CC=CC=1>[CH2:32]([O:31][N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:39])[CH2:22][CH2:21][C:20](=[O:40])[N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)O
Solvent: c1ccncc1
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Yield: 95 %

Procedure:
5,16-Bis(benzyloxy)-4,12,15-trioxo-5,11,16-triaza-19,22,25-trioxahexacosanoic acid (19) was synthesized by reacting compound (18) (3.40 g, 6.07 mmol) with succinic anhydride in pyridine following the procedure of (16) to produce 3.81 g (95%) of (19) as an oil: NMR δ 1.2-1.8 (m, 6 H), 2.38-2.91 (m, 8 H), 3.07-3.83 (m, 19 H), 4.79 (s, 2 H), 4.88 (s, 2 H), 5.7 (br s, 1 H), 6.62 (br s, 1 H), 7.33 (s, 10 H). Analysis: (C34H49N3O10) C, H, N.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([CH3:28])([C:26]#[CH:27])[C:22]([O:24][CH3:25])=[O:23]>>[C:15]([C:13]1[N:14]=[C:7]2[C:6]3[CH:18]=[C:2]([C:27]#[C:26][C:21]([OH:20])([CH3:28])[C:22]([O:24][CH3:25])=[O:23])[C:3]([F:19])=[CH:4][C:5]=3[O:11][CH2:10][CH2:9][N:8]2[CH:12]=1)(=[O:16])[NH2:17]
Reactant: C#CC(C)(O)C(=O)OC
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with methyl 2-hydroxy-2-methylbut-3-ynoate to give the titled compound as a brown oil. M+1=374
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:14]#[CH:15]>>[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[O:3])[CH2:18][CH2:17]1)[C:14]#[CH:15]
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccc(OC)cc2)CC1

Procedure:
4-(methoxy)phenyl chloroformate (5.00 g, 26.8 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.60 g, 20.9 mmol) according to general procedure 1. Yield=5.02 g, 90%. m/z MH+=274.06. HPLC rt=12.2 min.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:26]1[CH2:25][CH2:24][C@H:23]([CH2:22][CH2:21][N:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][CH2:3][C:2]2=[O:1])[CH2:28][CH2:27]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2C(=O)COc3ccc(C#N)cc32)CC1

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (350 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) afforded the product as a solid (50%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])[OH:3].[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:21]1[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]1)[OH:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(O)c1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)c1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-2-aminophenyl carbinol from Step 1 above (0.86 g, 6.3 mmol), N-Boc-4-piperidone (2.5 g, 12.6 mmol), and acetic acid (1.08 mL, 1.13 g, 18.9 mmol) were combined in methanol (10 mL). Sodium cyanoborohydride (0.79 g, 12.5 mmol) was added in portions, and the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo. Ethyl acetate (100 mL) was added to the residue and the resulting mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel eluted with 1:9 then 15:85 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give methyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH2:9])=[N:6][CH:7]=1.[C:10]([N+:14]#[C-:15])([CH3:13])([CH3:12])[CH3:11]>CO.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:9][N:8]=2)[CH:7]=1
Reactant: C=Nc1ccc(Br)cn1
Reactant: [C-]#[N+]C(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Nc1cnc2ccc(Br)cn12
Temperature: 25 °C
Yield: 78 %

Procedure:
To a suspension of 5-bromo-N-methylenepyridin-2-amine (0.85 g, 4.6 mmol) in methanol (20 mL) was added tert-butyl isocyanide (1.14 mL, 10.1 mmol) and trifluoroacetic acid (˜3 drops). The reaction mixture was heated at reflux for 2 h, after which point a clear solution was obtained. The mixture was allowed to cool to ambient temperature and was concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient ethyl acetate in hexanes to afford 6-bromo-N-(tert-butyl)imidazo[1,2-a]pyridin-3-amine as a beige solid in 78% yield (0.956 g): 1H NMR (300 MHz, CDCl3) δ8.31 (br s, 1H), 7.41-7.33 (m, 1H), 7.29 (s, 1H), 7.17-7.10 (m, 1H), 2.70 (br s, 1H), 1.16 (s, 9H); MS (ES+) m/z 267.9 (M+1), 270.0 (M+1).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][C:21]1([CH3:30])[N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:24]2[CH2:23][O:22]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]3[C:21]([CH3:30])([CH3:20])[O:22][CH2:23][CH:24]3[CH2:29]2)=[CH:7][CH:8]=1
Reactant: CC1(C)OCC2CNCCN21
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC2CN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CCN21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 30.7 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene], 11.5 parts of hexahydro-3,3-dimethyl-1H-oxazolo-[3,4-a]pyrazine, 14.8 parts of sodium carbonate and 270 parts of N,N-dimethylformamide was stirred for 5 hours at about 70° C. The reaction mixture was cooled overnight to room temperature and the solvent was evaporated. The residue was dissolved in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated, yielding 34 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-3,3-dimethyl-1H-oxazolo[3,4-a]pyrazine as a residue (intermediate 94).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].F[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:2]([CH2:3][CH2:4][CH:5]([O:6][C:22]1[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:1]
Reactant: CN(C)CCC(O)c1cccs1
Reactant: Fc1cccc2ccccc12
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1

Procedure:
In this example, 2-acetylthiophene is used as the starting material for reacting with formaldehyde and dimethylamine to form a Mannich product namely 3-dimethylamino-1-(2-thienyl)propan-1-one. A hydride reduction is performed on this propanone to form corresponding 3-dimethylamino-1-(2-thienyl)propan-1-ol. The resulting propanol is then reacted with fluoronaphthalene to form N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. Subsequently, racemic Duloxetine® is obtained by demethylation of this propylamine. In this process, the yield of demethylation is very low, about 41%. In addition, Duloxetine® produced via this route is racemic. Resolution is therefore needed to obtain chiral Duloxetine which renders this process less competitive.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH:87]1([NH:93][C:94](=[O:98])[C:95](O)=[O:96])[CH2:92][CH2:91][CH2:90][CH2:89][CH2:88]1>>[CH:87]1([NH:93][C:94](=[O:98])[C:95]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:96])[CH2:92][CH2:91][CH2:90][CH2:89][CH2:88]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)C(=O)NC1CCCCC1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C(=O)NC3CCCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(cyclohexylamino)-2-oxoacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 681.7 (M−H)−, 2.42 min (method 9). 1H NMR (500 MHz, CHLOROFORM-d) δ=8.03 (d, J=8.5 Hz, 2H), 7.61 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 6.51 (br. s., 1H), 5.33 (d, J=4.6 Hz, 1H), 4.79 (d, J=1.2 Hz, 1H), 4.67 (s, 1H), 3.83-3.72 (m, 1H), 2.62-2.54 (m, 2H), 2.50 (dd, J=8.5, 11.6 Hz, 1H), 2.14 (dd, J=6.3, 17.2 Hz, 1H), 2.00-1.89 (m, 3H), 1.86-1.75 (m, 4H), 1.71-1.62 (m, 2H), 1.61-1.36 (m, 13H), 1.35-1.20 (m, 5H), 1.18-1.11 (m, 2H), 1.08 (s, 3H), 1.05-1.02 (m, 3H), 1.00 (s, 3H), 0.96 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:12]([N+:14]([O-])=O)[CH3:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:13][CH:12]([CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)[NH2:14]
Reactant: CC(=Cc1c[nH]c2cc(F)ccc12)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(N)Cc1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 92.2 %

Procedure:
α-Methyl-6-fluorotryptamine was prepared by the dropwise addition of an anhydrous THF solution of 6-fluoro-3-(2-nitropropenyl)-1H-indole (560 mg, 2.54 mmol) to a stirred mixture of LiAlH4 (480 mg, 12.7 mmol) in THF (40 mL) at 0° C. The reaction slurry was allowed to stir under N2 from 0° C. to ambient room temperature over 3.5 hours. The reaction solution was again cooled to 0° C. prior to the dropwise addition of H2O to quench excess LiAlH4. The reaction suspension was filtered through a pad of Celite to remove Al salts. The filtrate was concentrated under reduced pressure, diluted with EtOAc (200 mL), washed with NaCl (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to provide 450 mg of α-methyl-6-fluorotryptamine as a viscous oil; 1H NMR (CDCl3) δ 8.30 (1H, br s), 7.52 (1H, m), 6.98-7.04 (2H, m), 6.87 (1H, t), 3.29 (1H, m), 2.87 (1H, dd), 2.64 (1H, q), 1.25 (3H, d); MS (ESI): 193 (MH+); TLC (SiO2 plate, 100% DCM) Rf=0.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:40][CH:41]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (521 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (731 mg, yield 68%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][C:28](=[O:30])[CH3:29]>>[CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]([CH2:27][C:28](=[O:30])[CH3:29])[CH:14]=[N:13][C:12]=3[N:11]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]2=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)CCl
Reactant: O=c1c2[nH]cnc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CCCCC1)c(=O)n2CC1CCCCC1

Procedure:
1,3-Di-cyclohexylmethyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclohexylmethyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 153° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C@H:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[CH2:17][CH:16]=2)=[CH:11][C:10]=1[NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])[CH3:36]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:17][CH:16]=2)=[CH:11][C:10]=1[NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])[CH3:36]
Reactant: C[C@@H](Nc1cc(C2=CCN([C@H]3CCCN(C(=O)OC(C)(C)C)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Nc1cc(C2=CCN([C@H]3CCCNC3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a solution of (S)-t-butyl 3-(4-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate (0.83 g, 1.5 mmol) in dichloromethane (3 mL) at room temperature, and the solution was stirred for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane. The organic layer was neutralized with aqueous saturated sodium bicarbonate solution, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (0.65 g, 1.4 mmol, 96%). MS: (ES) m/z calculated for C24H29ClN3 [M+H]+ 464.1. found 464.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:3])=[O:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccccc1[N+](=O)[O-])C(=O)OCC
Yield: 88 %

Procedure:
A mixture of 2-nitroaniline (41.4 g) and diethyl ethoxymethylenemalonate (66 ml) was heated on a steam bath for 24 hours. The hot reaction mixture was treated with ethanol (300 ml), cooled and filtered to give diethyl (2-nitroanilino)methylenemalonate in 88% yield, mp 104-105° C.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[Na+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(OCC)(=O)C>CN(C=O)C>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1C(=O)C(C)(C)c2cc(C3=NNC(=O)SC3C)ccc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
1.16 g 5-(3,6-Dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (Example 3) in 30 ml DMF were cooled to 0° C. 0.175 g sodium hydride from a 55% dispersion in mineral oil was added and the mixture was successively stirred for 0.5 hr at 0° C. and 0.5 hr at 20° C. After cooling to 0° C. a solution of 0.43 g ethyl chloroformate in 2 ml DMF was added dropwise. The reactional mixture was stirred at room temperature for 16 hrs, 250 ml ethyl acetate were added and the organic solution was washed with water. The aqueous phase was extracted with 2×100 ml methylene chloride and the organic solutions were mixed, dried on magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica (methylene chloride-ethyl acetate: 4/1) then washed with isopropyl ether to yield 1.11 g of crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][C@@H:24]([NH2:27])[CH2:25][OH:26])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[OH:26][CH2:25][C@H:24]([NH:27][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH2:23][S:20](=[O:21])(=[O:22])[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH:10]([CH3:11])[CH3:12])[CH2:14][CH2:15]1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)N1CCC(NS(=O)(=O)C[C@@H](N)CO)CC1
Product: CC(C)N1CCC(NS(=O)(=O)C[C@H](CO)NC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [(S)-1-hydroxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 26 viii) starting from 28 mg (1.1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 44 mg (0.16 mmol) (S)-2-amino-3-hydroxy-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [(S)-1-hydroxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][N:12]=1)[CH3:2].[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)=[N:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Reactant: O=C(O)C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CCC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3,4-thiadiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D27) (100 mg, 0.266 mmol) in Ethanol (10 mL) stirred at room temperature was added 3-pyrrolidinecarboxylic acid (123 mg, 1.065 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)methyl]-3-pyrrolidinecarboxylic acid (E48) (55 mg) as a off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12]>O1CCCC1>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH:16][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Add 24.4 g (0.154 mol) of p-fluorobenzoyl chloride in 100 mL of tetrahydrofuran dropwise to 17.88 g (0.154 mol) of N,N-diethylethylenediamine in 150 mL of tetrahydrofuran at 0° C. Stir at 0° C. for about 2 hr then at room temperature for about 17 hr. Concentrate the resultant solution and treat the residue with 1N NaOH until about pH=10. Extract the resultant solution with methylene chloride (2×100 mL). Dry the extract with Na2SO4 amd evaporate the solvent to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[S:7](=[O:9])(=[O:8])[NH:6][C:5]([O:10][CH3:11])=[N:4][C:3]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)=O>>[Cl:14][C:3]1[N:2]([CH3:1])[S:7](=[O:9])(=[O:8])[N:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: COC1=NC(=O)N(C)S(=O)(=O)N1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Temperature: 110 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
215 parts of 6-methyl-3-methoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide were introduced into a stirred mixture of 275 parts of phosphorous pentachloride in 1,480 parts of phosphorus oxychloride at room temperature, and the batch was heated to 110° C. in the course of 30 minutes. After 4 hours' stirring under reflux, the reaction mixture was concentrated under reduced pressure, giving 235 parts (99.6% of theory) of 5-chloro-6-methyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 77°-83° C.