Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[CH2:8]([NH:11][C@H:12]([CH2:16][OH:17])[CH2:13][CH2:14][CH3:15])[CH2:9][CH3:10].[S:18](Cl)(Cl)=[O:19].O>ClCCl>[CH2:8]([N:11]1[CH:12]([CH2:13][CH2:14][CH3:15])[CH2:16][O:17][S@@:18]1=[O:19])[CH2:9][CH3:10]
Reactant: CCCN[C@H](CO)CCC
Reactant: O=S(Cl)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CCCC1CO[S@](=O)N1CCC
Temperature: 25 °C
Yield: 79 %

Procedure:
N-Methylmorpholine (27.3 mL) was added to a solution of (S)—N-propylnorvalinol (11.5 g) in dichloromethane (200 mL) under stirring at room temperature. A solution of thionyl chloride (9.32 mL) in dichloromethane (64 mL) was added dropwise to the resulting light yellow solution under ice-cooling and stirring. The resulting suspension was stirred at room temperature. Water was added to the suspension under ice-cooling and stirring, and the mixture was extracted with dichloromethane. The organic layer was washed with an aqueous 1 mol/L hydrochloric acid solution and subsequently with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was dried under reduced pressure at room temperature overnight to give (S)-3,4-dipropyl-1,2,3-oxathiazolidine 2-oxide as a colorless oil (16.1 g, 79% yield, cis:trans=about 38:62 determined from the integration ratio in 1H-NMR).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:31])=[N:23][C:24]=2[NH:28][O:29][CH3:30])(=O)C>N>[OH:15][CH2:14][C@H:8]1[O:7][C@@H:6]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:31])=[N:23][C:24]=3[NH:28][O:29][CH3:30])[C@H:5]([OH:4])[C@@H:9]1[OH:10]
Reactant: CONc1nc(I)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Product: CONc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 96 h

Procedure:
Methanolic ammonia (30 mL) was added to (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-[2-iodo-6-(methoxyamino)purin-9-yl]oxolan-3-yl acetate (3.03 mmol). The mixture was allowed to stand at room temperature for 96 hours, then solvent was removed in vacuo and the residue chromatographed on a flash silica gel column eluting with CHCl3—CH3OH (97:3) to give the compound of formula (5), (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[2-iodo-6-(methoxyamino)purin-9-yl]oxolane-3,4-diol, which was crystallized from acetonitrile,.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][O:19][CH2:20][C@@H:21]([C:30]([OH:32])=[O:31])NC(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:40]C(N1CCC(CCOC[C@H](C(O)=O)NC(OC(C)(C)C)=O)CC1)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][O:19][CH2:20][C@H:21]([OH:40])[C:30]([OH:32])=[O:31])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](COCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Product: O=C(O)[C@@H](O)COCCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
0.5 g of O-[2-(1-benzyloxycarbonyl-4-piperidyl)ethyl]-N-(tert-butoxycarbonyl)-L-serine, in place of O-[2-(1-benzyloxycarbonyl-4-piperidyl)ethyl]-N-(tert-butoxycarbonyl)-D-serine, is subjected to the same reaction procedure and purification treatment as in Reference Example 7 to give 380 mg of 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethoxy]-2(S)-hydroxypropionic acid as an oily substance.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH:32]([CH3:34])[CH3:33])[NH:17][CH:16]2[C:37]([OH:39])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:46][C@H:45]([CH2:47][CH2:48][NH2:49])[CH2:44][O:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:46][C@@H:45]([CH2:44][OH:43])[CH2:47][CH2:48][NH:49][C:37]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:40])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:36])[CH:32]([CH3:34])[CH3:33])[NH:17]1)=[O:39]
Reactant: CC1(C)OC[C@@H](CCN)O1
Reactant: CC(C)C(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C)(C)CC1NC(C(=O)NCC[C@@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 57.2 %

Procedure:
In a manner similar to the method described in Example 72a rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.39 g, 2.7 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:25]2[CH2:26][CH2:27][CH:22]([C:19]3[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=3)[CH2:23][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Yield: 37.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (2.59 g) and 4-(4-pyridyl)piperidine (1.97 g) in methanol/acetic acid (99:1) (50 ml) was added sodium cyanoborohydride (2.29 g) portionwise over 30 minutes and the resultant suspension stirred at ambient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated, The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 1-[1-tert-butoxycarbonyl(4-piperidinylmethyl)]-4-(4-pyridyl)piperidine (1.65 g) as a solid: NMR (CDCl3): 1.10 (m, 2H), 1.40 (s, 9H), 1.75 (m, 7H), 2.00 (dt, 2H), 2.20 (d, 2H), 2.45 (m, 1H), 2.70 (m, 2H), 3.00 (d, 2H), 4.10 (m, 2H), 7.20 (d, 2H), 8.50 (d, 2H); m/z 360 (M+1).
Reaction SMILES: [Na].[C:2]([NH2:8])(=[O:7])[CH2:3][C:4]([NH2:6])=[O:5].C(O[C:12](=O)[CH2:13][NH:14][C:15](=[O:21])[C:16]1[S:20][CH:19]=[CH:18][CH:17]=1)C.C(O)(=O)C>C(O)C.O>[C:16]1([C:15]([NH:14][CH2:13][C:12]2[N:6]=[C:4]([OH:5])[CH:3]=[C:2]([OH:7])[N:8]=2)=[O:21])[S:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)CC(N)=O
Reactant: CCOC(=O)CNC(=O)c1cccs1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(NCc1nc(O)cc(O)n1)c1cccs1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of sodium (1.4 g) in ethanol (120 ml) was added malonamide (3.8 g) and the mixture was heated at 60° C. for an hour under stirring. Then after added N-(2-thenoyl)glycine ethyl ester (8 g), the mixture was refluxed for 6 hours. The mixture was concentrated to give the residue which was diluted with water. The aqueous mixture was neutralized by adding acetic acid to deposit a crystalline product which was collected by filtration and recrystallized from dimethylformamide (DMF) to give the objective product (2.8 g) as colorless crystals, mp 270°-275° C. (decompd.).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.Cl>C1COCC1>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[Cl:1])=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1cccnc1Cl
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
2-Chloronicotinic acid (2.5 grams, 15.9 mmol) and 80 ml THF is placed in a 250 ml three neck round bottom flask equipped with mechanical stirring, a thermometer and a rubber septum with a nitrogen inlet. The reaction mixture is cooled to -5° C. and N-methylmorpholine (1.6 grams, 15.9 mmol) added via syringe. Isobutyl chloroformate (2.2 grams, 15.9 mmol) is then added via syringe while maintaining the temperature below 0° C. The reaction is stirred for 30 minutes at -5° C. The p-fluorobenzylamine (2.2 grams, 17.5 mmols) is then added via syringe, keeping the temperature below 0° C. The reaction is allowed to warm to room temperature and stirred for 18 hours, after which 1M HCl (30 ml) is added. This is then extracted with ethyl acetate (2×30 ml), and the combined organics washed with 1M HCl (1×30 ml), 3M NaOH (2×30 ml), H2O (1×50 ml) and brine (1×50 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to a yellow solid. This is triturated with diethyl ether, filtered, washed with fresh diethyl ether and dried in vacuo to yield 3.4 g (80.5%) of the desired chloronicotinamide as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](Br)=[N:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCN2C=NC=C2C1)C1C=CC=CC=1.C([Li])CCC.[Br:39]Br>C1COCC1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[N:15][C:16]([Br:39])=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Brc1ncc2n1CCN(Cc1ccccc1)C2
Agent: [Li]CCCC
Agent: c1ccc(CN2CCn3cncc3C2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1ncn2c1CN(Cc1ccccc1)CC2
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
7-Benzyl-3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine: The synthesis of 7-benzyl-3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine is described in PCT/IB03/00998 WO 03/076427 A1. A solution of 7-benzyl-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazine (450 mg, 2.110 mmol) in THF was cooled in dry ice acetone bath. n-Butyllithium (0.928 mL, 2.321 mmol) was added dropwise. After 15 mins, bromine (0.120 mL, 2.321 mmol) was added dropwise. After 1 h, the solution was poured into H2O and extracted with DCM (3×). Purified by normal phase chromatography to afford 7-benzyl-1-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (112 mg, 0.383 mmol, 18.2% yield) and 71A (260 mg, 0.890 mmol, 42.2% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.44 (m, 5H) 6.71 (s, 1H) 3.78-3.95 (m, 2H) 3.68 (s, 2H) 3.60 (s, 2H) 2.75-2.97 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH:11]1[CH2:14][O:13][CH2:12]1)[C:7]([O:9]C)=[O:8])=[O:4].O.[OH-].[Li+:17].S(=O)(=O)(O)O.[Li+].[OH-]>C1COCC1.O.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O.CC(=O)OCC>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH:11]1[CH2:12][O:13][CH2:14]1)[C:7]([O-:9])=[O:8])=[O:4].[Li+:17]
Reactant: COC(=O)NC(C(=O)OC)C1COC1
Agent: O=[Mo](=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)[O-])C1COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowed to stir overnight at ambient temperature. TLC (1:1 EA/Hex; Hanessian stain [1 g Ce(NH4)2SO4, 6 g ammonium molybdate, 6 ml sulfuric acid, and 100 ml water]) indicated ˜10% starting material remaining. Added an additional 3 mg LiOH and allowed to stir overnight at which time TLC showed no starting material remaining. Concentrated in vacuo and placed on high vac overnight providing 55 mg lithium 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless solid. 1H NMR (500 MHz, MeOD) δ ppm 3.39-3.47 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.93 Hz, 1H) 4.64 (t, J=6.26 Hz, 1H) 4.68 (t, J=7.02 Hz, 1H) 4.73 (d, J=7.63 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][NH2:20])[CH3:16].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][C:5]([C:6]([NH:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:15][CH3:16])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Cl)c(C#N)cc1C(=O)Cl
Reactant: CCN(CC)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1cc(C#N)c(Cl)cc1OC

Procedure:
While stirring under nitrogen, at minus 30°, a solution of 23 g (0.1 mol) of 4-chloro-5-cyano-2-methoxybenzoic acid chloride in 70 ml of methylene chloride is added dropwise to a solution of 11.6 g (0.1 mol) of 2-diethylaminoethylamine in 100 ml of methylene chloride. The resulting white suspension is then stirred at room temperature for 15 hours, 105 ml (0.105 mol) of 1M sodium hydroxide solution are then added dropwise thereto and the whole is stirred until 2 distinct layers have formed and then separated in a separating funnel, and the aqueous phase is again extracted by shaking with 50 ml of methylene chloride. The combined organic phases are dried over magnesium sulphate and filtered, 150 ml of cyclohexane are added and methylene chloride is distilled off until the distillation temperature is 70°. After cooling, the base that has crystallised out is filtered off with suction and then washed with cyclohexane. After drying, 4-chloro-5-cyano-N-(2-diethylaminoethyl)- 2-methoxybenzamide having a melting point of 104°-105° is obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[C:57]([O:61][C:62](=[O:71])[NH:63][C@H:64]1[CH2:69][CH2:68][C@@H:67]([NH2:70])[CH2:66][CH2:65]1)([CH3:60])([CH3:59])[CH3:58].[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[C:57]([O:61][C:62](=[O:71])[NH:63][C@H:64]1[CH2:65][CH2:66][C@@H:67]([NH:70][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:68][CH2:69]1)([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 3 h

Procedure:
To a mixture of 0.112 g (0.15 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.099 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 2 mL of dichloromethane, 0.3 mL of triethylamine was added followed by 0.051 g (0.24 mmole) of cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester. After 3 hours, 4 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 100:0-0:100) to give 0.0673 g of cis-{4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (I-97).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[C:9]([CH3:13])[S:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[C:9]([CH3:13])[S:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2c(C)sc3cc(OC)ccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1sc2cc(O)ccc2c(=O)c1-c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 70 %

Procedure:
Synthesis: Step 1: Synthesis of methyl 4-(7-methoxy-2-methyl-4-oxo-4H-thiochromen-3-yl)benzoate: To a solution of Intermediate F (methyl 4-(2-(2-(acetylthio)-4-methoxyphenyl)-2-oxoethyl)benzoate) (600 mg, 1.674 mmol) in acetone (12 ml) was added K2CO3 (386 mg, 3.348 mmol) at room temperature. The mixture was stirred for 3 hours, filtered and concentrated. The residue was purified by Combi-Flash (40 g silica gel, start PE/EtOAc=10/0 to 3/1 gradient, 40 ml/min, 40 min, 1.6 L total solvent volume) to afford the product as a yellow solid (400 mg, 70%). MS (ESI): m/z 341.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH2:63])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1>CN(C=O)C>[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH:63][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-(methoxycarbonyl)benzoic acid (18 mg, 0.1 mmol), HATU (41.8 mg, 0.11 mmol), and diisopropylethylamine (39 mg) in DMF was stirred at RT for 5 min. A syn and anti mixture of 6-(2-(dimethylamino)-1-(1H-Imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (31.5 mg, 0.1 mmol) in DMF was added and stirred at RT. DMF was evaporated and the residue was purified by PTLC using 10% methanol in DCM as eluent to afford the syn and anti isomers of methyl 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate. ESI: m/z 478.2 [M+1+].
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)=O.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: COCCO
Reactant: Clc1ccncc1
Agent: O=C=O
Agent: [Na]
Product: COCCOc1ccncc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (9.96 g) in 2-methoxyethanol (100 ml) was added dropwise 4-chloropyridine (42.7 g) under heating at 140° to 145° C. and stirring, which was continued for one hour at 135° C. after the addition. The mixture was cooled to -15° C. and dry ice (5.6 g) was added thereto. The mixture was warmed to 45° C. and then allowed to stand at room temperature. The resulting precipitates were removed by filtration and washed with diisopropyl ether. The filtrate and washings were combined and evaporated. The residual oil was distilled to give 4-(2-methoxyethoxy)pyridine (42.3 g), bp. 98° to 106° C. at 6 mmHg.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[Br:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:3]=1[C:30]#[N:31].P(O)(O)[OH:33]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[Br:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:3]=1[C:30]([NH2:31])=[O:33]
Reactant: OP(O)O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2Br)c1N
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2Br)c1N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (137 mg, 0.287 mmol) in phosphorous acid (85 wt. % in H2O, 10 mL) was stirred at 100° C. for 1 hr, until TLC and LCMS analysis showed that most of starting material was consumed. The reaction was cooled to room temperature and partitioned between water (40 mL) and EA (40 mL). Organic layer was separated from aqueous layer. The aqueous phase was then extracted with EA (20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to get the crude product (149 mg) which was used in next step without further purification. MS (ESI) m/e [M+1]+494, 496.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]([CH3:34])[C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:36](Cl)(=[O:38])[CH3:37]>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:36](=[O:38])[CH3:37])[C@@H:25]([CH3:34])[C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H](C)[C@H](O)c2ccccc2)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H](C)[C@H](O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[((1S,2R)-2-hydroxy-1-methyl-2-phenyl-ethylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]([NH2:34])=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:23]([NH:34][C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:12])=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: CC(C)(C)OC(=O)Nc1cc(NCc2ccccc2)c(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2cnc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (3.589 g; 21.47 mmol) and (5-amino-4-benzylamino-pyridin-2-yl)-carbamic acid tert-butyl ester E-2.11 (4.500 g; 14.31 mmol) are dissolved in THF and and cooled to 0° C. DIPEA (5.539 g; 42.94 mmol) and HATU (10.878 g; 28.63 mmol) are added. The mixture is stirred at room temperature for 1 hr. Water is then added to the reaction mixture, precipitation of the product occurs. The precipitate is filtered off and dried under vacuum. The residue is used in the next step without further purification.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=[N:2]1.[CH2:13](Br)[CH3:14]>>[CH2:13]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[S:1](=[O:12])(=[O:11])[N:2]=[CH:3]1)[CH3:14]
Reactant: CCBr
Reactant: O=S1(=O)N=CNc2cccnc21
Product: CCN1C=NS(=O)(=O)c2ncccc21

Procedure:
The compound is obtained according to the same procedure as that described for Example 63, starting from 0. 1 g of 4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 16) and 0.17 g of ethyl bromide.