Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:19]([O:21][CH2:22][CH:23]([CH2:25][O:26][C:27](=[O:40])[C@H:28]([CH:37]([CH3:39])[CH3:38])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[OH:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:24][CH:23]([CH2:25][O:26][C:27](=[O:40])[C@H:28]([CH:37]([CH3:39])[CH3:38])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][O:21][C:19](=[O:20])[C@H:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:12]([O:11][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:13])=[O:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
Chloromethyl chloroformate (2.70 mL, 30 mmol) was added to a solution of 1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (7.27 g, 14.8 mmol) and pyridine (7.2 mL, 89 mmol) in 60 mL dry CH2Cl2, in an ice bath, under N2. After stirring for 1 h 45 min, the reaction mixture was diluted with 100 mL CH2Cl2 and washed with 40 mL water. The aqueous phase was reextracted with 20 mL H2O. The organic phases were combined, washed with 40 mL saturated NaHCO3, followed by 2×50 mL brine, dried over Na2SO4, and concentrated under vacuum. Flash column chromatography on silica gel with 2/1 hexane-EtOAc gave 8.03 g (93%) of the title compound (alternative nomenclature: 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl chloromethyl carbonate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:16]([CH:11]1[C:10](=[O:15])[CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][C:12]1=[O:14])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=C1CC(=O)CC(c2cccc(F)c2)C1
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2cccc(F)c2)CC1=O

Procedure:
The title compound was prepared from 5-(3-fluoro-phenyl)-cyclohexane-1,3-dione (500 mg, 2.48 mmol), example 1/d stage 2, and sodium acetate (204 mg, 2.48 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (example 3/a stage 1).
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25].C(N(CC)CC)C.[P:33]([O-:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:35]([O:34][P:33]([C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:36]
Reactant: CCOP([O-])OCC
Reactant: Cc1c(I)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1nc2n(c1C)N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Yield: 10.1 %

Procedure:
100 mg of 9-iodo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is stirred in 2 ml of dimethylformamide, 0.03 ml of triethylamine, 0.032 ml (30 mg) of diethyl phosphite and 15 mg of tetrakis(triphenylphosphine)-palladium(O) at 1000° C. for 2 hours. Then, it is diluted with 10 ml of water and extracted with ethyl acetate. The organic phase that is concentrated by evaporation is chromatographed on silica gel with dichloromethane:ethanol=95:5 as an eluant. 10 mg of 8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine-9-phosphonic acid diethyl ester is obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]2[CH:22]=[CH:23][S:24][C:14]=12.C(N(CC)CC)C>C(O)(C)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:13]3[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]4[CH:22]=[CH:23][S:24][C:14]=34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: NC1CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1NC1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-amine (from J&W PharmLab, 0.40 g, 2.5 mmol), 7-chloro-6-nitrothieno[3,2-b]pyridine (0.29 g, 1.4 mmol) and triethylamine (0.38 mL, 2.7 mmol) in isopropyl alcohol (4.4 mL) was stirred at 90° C. for 2 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C15H18N3O4S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][O:10][C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=4[NH:16][C:15]=3[N:14]=[CH:13][CH:12]=2)([CH3:8])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[Br:31]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:31][C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:17]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[C:19]=2[C:11]=1[O:10][CH2:9][C:5]1([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC(C)(COc2c(Br)cnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.7 %

Procedure:
A mixture of 4-((1,4-dimethylpiperidin-4-yl)methoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.16 mmol), sodium acetate (26 mg, 0.3 mmol), and bromine (32 L, 0.6 mmol) in acetic acid (1 mL) was stirred at ambient temperature for 10 minutes. The reaction mixture was diluted with water (1 mL) and basified to pH ˜8 by dropwise addition of 6N sodium hydroxide solution, producing a yellow precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (25 mg, 38%). 1H NMR (500 MHz, d6-DMSO) δ 9.02 (d, J=8.7, 1H), 8.70 (d, J=9.9, 1H), 8.43 (s, 1H), 4.21 (s, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 2.45 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 1.30 (s, 3H), NH signal not observed. LCMS (Method D): RT=8.660 min, M+H+=414.0/416.0.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([F:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[NH2:35][C:36]1[CH:48]=[C:47]([N:49]2[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>ClCCl.C(OCC)(=O)C>[F:8][C:9]1([F:16])[CH2:14][CH2:13][CH:12]([NH:35][C:36]2[CH:48]=[C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH:46]=[CH:45][C:37]=2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:11][CH2:10]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: O=C1CCC(F)(F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(NC3CCC(F)(F)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.9 %

Procedure:
1.045 ml (13.57 mmol) of trifluoroacetic acid, 1 g (7.46 mmol) of 4,4-difluorocyclohexanone and 2.158 g (8.20 mmol) of tetramethylammonium triacetoxyborohydride are added to 1.521 g (5.22 mmol) of tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate dissolved in 60 ml of dichloromethane. The reaction is left under stirring at room temperature for 24 hours. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solution is successively washed with 0.5 M HCl solution, 0.5 M soda solution and finally with saturated NaHCO3 solution. The organic phase is dried on sodium sulfate, filtered and concentrated to obtain 2.2 g of tert-butyl 2-(4,4-difluorocyclohexylamino)-4-(4-methylpiperazin-1-yl)benzoate in the form of a light brown gum (yield=72%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.Cl.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[N:23]=[C:22]([CH:24]2[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]2)[O:21][N:20]=1.C(N(CC)CC)C.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>C1(C)C=CC=CC=1.ClCCl>[CH:37]1([NH:40][C:5]([N:27]2[CH2:28][CH2:29][CH:24]([C:22]3[O:21][N:20]=[C:19]([C:15]4[S:14][CH:18]=[CH:17][CH:16]=4)[N:23]=3)[CH2:25][CH2:26]2)=[O:11])[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
54.60 mg (1 eq.) of triphosgene were added to a suspension of 150 mg (3 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride and 102.63 μl (4 eq.) of triethylamine in 2 ml of toluene. The reaction medium was stirred overnight at room temperature and then filtered. The filtrate thus collected was concentrated under reduced pressure. The residue obtained was taken up in 2 ml of dichloromethane, followed by addition of 77 μL (1 eq.) of triethylamine and 77.44 μl (2 eq.) of cyclopropylamine. The reaction medium was stirred for 20 hours at room temperature and then concentrated to dryness. The residue was chromatograph on a thick layer of silica (eluent: CH2Cl2/MeOH (95/5; v/v)) to give 80 mg (45%) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].Br[CH2:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.O>C(O)C>[C:14]([C:13]1[NH:6][C:5]2[C:7]([CH:12]=1)=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COc1cc(N)ccc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc2[nH]c(C(C)(C)C)cc2cc1Cl

Procedure:
A solution of 4-chloro-3-methoxyaniline (4.68 g) in ethanol (4.5 mL) was heated under reflux while stirring. To the solution was added 1-bromo-3,3-dimethyl-2-butanone (0.243 mL×5) in five portions at an interval of 5 minutes, and this mixture was heated under reflux while stirring for 4 hours. The reaction mixture was left to be cooled. To the reaction mixture were added 2 mol/L hydrochloric acid and water successively, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (893 mg). 1H-NMR (CDCl3) δ ppm: 1.37 (9H, s), 3.89 (3H, s), 6.09-6.16 (1H, m), 6.88 (1H, s), 7.50 (1H, s), 7.72-8.12 (1H, br).
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[N:5])[CH3:2].[Cl:9][CH2:10][CH2:11]O>O.[Cl-].[Zn+2].[Cl-].[Zn]>[Cl:9][CH2:10][CH2:11][O:8][C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[C:4]#[N:5]
Reactant: CCC(O)(C#N)CC
Reactant: OCCCl
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: CCC(C#N)(CC)OCCCl
Temperature: 60 °C
Reaction time: 20 h
Yield: 39471.1 %

Procedure:
Zinc chloride (68.1 g, 0.5 mol) was fused under vacuum as described in the procedure for the synthesis of intermediate 23. The molten zinc was cooled and the evacuated flask was flushed with nitrogen. The flask was loaded with intermediate 28, 2-ethyl-2-hydroxybutanenitrile, (40.3 g, 0.5 mol) and 2-chloroethanol (50.5 mL, 0.75 mmol) then stirred at 60° C. for 20 hours. The reaction mixture was diluted with water (250 mL) and extracted with dichloromethane (1×250 mL, 4×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated in-vacuo. The crude product was purified by vacuum distillation (bp 83° C., 10 mmHg) to give the title compound (52 g) containing unreacted intermediate 28. 1H NMR (500 MHz, CDCl3) δ ppm: 3.82 (2H, t, J=5.8 Hz), 3.64 (2H, t, J=5.8 Hz), 1.83 (4H, J=7.3 Hz), 1.03 (6H, t, J=7.6 Hz).
Reaction SMILES: O[C:2]1[C:7]([I:8])=[C:6]([OH:9])[CH:5]=[CH:4][N:3]=1.[C:10]([O-:13])([O-])=O.[Cs+].[Cs+].[CH3:16]I>CN(C=O)C>[CH3:2][N:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:16])=[C:7]([I:8])[C:10]1=[O:13]
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Oc1ccnc(O)c1I
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccn(C)c(=O)c1I
Temperature: 40 °C
Reaction time: 72 h

Procedure:
A mixture of 2,4-dihydroxy-3-iodopyridine(1.0 eq), Cs2CO3 (2.0 eq), MeI (10.0 eq) and anhydrous DMF was stirred at 40° C. for 72 h, and then the DMF and remaining MeI were evaporated. The residue was treated with aqueous NaS2O3, and the mixture was extracted five times with CH2Cl2. The CH2Cl2 extracts were treated with MgSO4, filtered, and evaporated. The residue was recrystallized from hexanes/CH2Cl2 to give 1-methyl-3-iodo4-methoxypyridin-2-one.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:4][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)(=[S:3])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CC([O-])=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=S)OCc1ccccn1
Yield: 91.3 %

Procedure:
Potassium thioacetate (8.4 g, 73 mmol), 2-picolyl chloride hydrochloride 1 (6.0 g, 37 mmol) and potassium carbonate (5.0 g, 37 mmol) were stirred in DMF (35 mL) at room temperature (20-22°) for 18 h. The reaction mixture was poured into water (200 mL). The resultant mixture was extracted with Et2O (2×50 mL). The combined organic phases were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2-picolyl thioacetate as a pale brown liquid (5.65 g). The product was used without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:5]2[CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:21]([N:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=2[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:21]([N:28]1[C:36]2[C:31](=[C:32]([NH:37][C:12]([C:9]3[N:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]4=[N:11][CH:10]=3)=[O:14])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1ccn2c(C(=O)O)cnc2c1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
To a solution of 7-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid (0.0527 g, 0.282 mmol) in 0.200 mL of CH2Cl2 was added a drop of DMF followed by oxalyl chloride (1.1 equivalents, 2M CH2Cl2). The reaction was stirred for 5 minutes until bubbling ceased. 1-Benzyl-1H-indazol-4-amine (0.0629 g, 0.282 mmol) was added as a solution in 0.600 mL of CH2Cl2 followed by DIEA (1.2 equivalents). The reaction was stirred at ambient temperature overnight. The reaction was concentrated and the solids were washed with Et2O, water, 2M Na2CO3, water, and finally with Et2O again to provided the desired product as a beige solid 0.072 g (65%). MS (ES+APCI) m/z=393 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[NH:12][C:11]([C:13](=[O:24])[NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[N:10][C:9]=12)=[O:4].Br[CH2:26][C:27]1[CH:31]=[C:30]([C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[O:29][N:28]=1.CC#N.O>C(O)=O>[Cl:37][C:34]1[S:33][C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:12]3[C:8]4=[CH:7][S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]4[N:10]=[C:11]3[C:13](=[O:24])[NH:14][CH:15]3[CH2:16][CH2:17][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][CH2:20]3)[CH:31]=2)=[CH:36][CH:35]=1.[Cl:37][C:34]1[S:33][C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:10]3[C:9]4=[C:5]([C:3]([OH:2])=[O:4])[S:6][CH:7]=[C:8]4[N:12]=[C:11]3[C:13](=[O:24])[NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:17][CH2:16]3)[CH:31]=2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1scc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Solvent: O=CO
Solvent: CC#N
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)scc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3csc(C(=O)O)c3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid were prepared by a procedure according to example 81 starting from 500 mg (1.40 mmol) 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid methyl ester and 397.4 mg (1.40 mmol) 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole. Hydrolysis of the resulting esters and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[Cl:23][CH2:24][C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)=[O:26].CC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:23][CH2:24][C@H:25]([C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)[OH:26]
Reactant: O=C(CCl)C1CCc2cc(F)ccc2O1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O[C@H](CCl)[C@H]1CCc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of (+)-B-chlorodiisopinocampheylborane [(+)-DIP-Chloride™] (2.10 g, 6.55 mmoles) in toluene (7 ml) is cooled to 0° C. under nitrogen atmosphere. On the magnetically stirred solution is added in 3 hours a solution of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanone (1.0 g, 4.373 mmoles) in toluene (3 ml). At the end of the addition, the mixture is stirred at 0° C. for further 20 hours. On the reaction mixture is added acetone (0.5 g), followed by a 10% w/w (5 ml) aqueous solution of sodium carbonate, and then demi water (5 ml). The reactive mixture is heated to 20° C. at the end of the additions and transferred in a separator funnel. The mixture is diluted with demi water (5 ml) and toluene (5 ml) and phases are separated. The organic layer is then washed with additional demi water (15 ml) and concentrated and anhydrified under vacuum to obtain crude (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol (99% de via GC). The product is purified by chromatography on silica using a toluene:ethyl acetate 9:1 eluting mixture. After separation, the product (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol is isolated as a colorless oil (0.64 g, 63%).
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[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:34]1[C:38]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.[CH:67]([N:70]([CH:73]([CH3:75])C)[CH2:71]C)(C)C.CN(C)CCN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[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]([NH:34][CH2:38][CH2:75][CH2:73][N:70]([CH3:67])[CH3:71])=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: CN(C)CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
To a mixture of 0.040 g (0.0899 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-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0120 g (0.134 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0244 g 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)-N-(3-dimethylamino-propyl)-3-ethyl-benzamide (I-199) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To the product of Example 5 (0.35 g, 0.0006 mole) in H2O (40 ml) and CH3CN (5 ml) was added LiOH (70 mg, 0.0017 mole). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to ≃4.5 with TFA and the product was isolated by RPHPLC to yield (±)β-[[2-[[[3-[(aminoiminomethyl)-amino]phenyl]carbonyl]amino]acetyl]amino]-1,3-benzodioxole-5-propanoic acid, trifluoroacetate salt (280 mg) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: C(OC([N:8]([CH2:15][CH3:16])[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:15]([NH:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH3:16]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-methyl 2-(tert-butoxycarbonyl(ethyl)amino)propanoate (4.40 g, 19.0 mmol) was dissolved in dichloromethane and treated with TFA (10 mL). The reaction mixture was stirred for 2 h at room temperature and concentrated in vacuo. The residue was diluted with brine and NaOH (aq. 50%) was added dropwise until pH=12.5. This was extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as an opaque liquid (1.85 g, 74%). [M+H] calc'd for C6H13NO2, 132; found, 132.