Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([C:31]#[N:32])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)=[O:12].C(N(C(C)C)CC)(C)C.[F:42][C:43]([F:53])([F:52])[C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Br)=[CH:46][CH:45]=1>ClCCl>[CH:28]([C:27]1[C:21]2[O:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:2]4[CH2:3][CH2:4][C:5]5([CH2:10][CH2:9][N:8]([CH2:48][C:47]6[CH:46]=[CH:45][C:44]([C:43]([F:42])([F:52])[F:53])=[CH:51][CH:50]=6)[CH2:7][CH2:6]5)[CH2:1]4)=[O:12])=[CH:18][CH:17]=3)=[N:23][C:22]=2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(Cc6ccc(C(F)(F)F)cc6)CC5)C4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 2-[4-(2,8-diazaspiro[4.5]dec-2-ylcarbonyl)phenyl]-7-isopropyl-1,3-benzoxazole-5-carbonitrile (25 mg, 0.046 mmol, EXAMPLE 121, Step B) in dichloromethane (2 ml) were added diisopropylethylamine (20 μl, 0.115 mmol) and 4-(trifluoromethyl)benzyl bromide (17 mg, 0.071 mmol). The mixture was stirred at room temperature overnight, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (21.4 mg, 0.036 mmol, 79% yield). Mass spectrum (ESI) 587.3 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:37]=[CH:36][C:35]([C:38]2[N:43]=[C:42]3[N:44]=[C:45]([SH:55])[N:46](COCC[Si](C)(C)C)[C:41]3=[CH:40][C:39]=2[Cl:56])=[CH:34][CH:33]=1.[Si](O[C@H:71]1[C@H:75]2[O:76][CH2:77][C@H:78]([OH:79])[C@H:74]2[O:73][CH2:72]1)(C(C)(C)C)(C)C>C1COCC1>[C:32]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:37]=[CH:36][C:35]([C:38]2[N:43]=[C:42]3[N:44]=[C:45]([S:55][C@H:71]4[C@H:75]5[O:76][CH2:77][C@@H:78]([OH:79])[C@H:74]5[O:73][CH2:72]4)[NH:46][C:41]3=[CH:40][C:39]=2[Cl:56])=[CH:34][CH:33]=1
Reactant: C[Si](C)(C)CCOCn1c(S)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Sc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (34.1 mg, 0.130 mmol) and DEAD (0.021 ml, 0.130 mmol) were added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-2-thiol (30.4 mg, 0.065 mmol) and (3S,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (25.4 mg, 0.097 mmol) in THF (1 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative TLC, eluting with EtOAc/isohexane (2:8) to give the title compound. LC-MS: calculated for C36H48ClN3O4SSi2 709.26 observed m/e: 710.42 (M+H)+ (Rt 1.59/2 min);
Reaction SMILES: FC1(F)CCN(C(C2NC3C(C=2)=CC(O[CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=CC=3)=O)CC1.[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=2)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([O:44][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1)=[C:39]([Cl:45])[CH:38]=2)=[O:34])[CH3:31]
Reactant: CCOC(=O)c1cc2cc(O)c(Cl)cc2[nH]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2[nH]1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 2, the title compound was synthesized from 6-chloro-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (example 39, step 2). The title compound was obtained in 66% yield as light yellow foam. MS (m/e): 365.0 (MH+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14](=O)[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[N:25][OH:26])[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Yield: 76.5 %

Procedure:
A mixture of 2 g (6.1 mmol) 1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone, 0.869 g (12.5 mmol) hydroxylamine, hydrochloride and 1.03 g (12.5 mmol) sodium acetate in 25 mL ethanol was heated to reflux for 2 h. After cooling to room temperature water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a ethyl acetate. The product containing fractions were evaporated to yield 1.6 g (77%) of the title compound as colorless viscous oil. MS (m/e): 343.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][N:5]=[C:4](C#N)[CH:3]=1.IC1C(N)=CC([NH:23][C:24]([CH3:31])([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:25])=NC=1>>[CH3:25][C:24]([NH:23][C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([C:8]#[C:9][Si:10]([CH3:11])([CH3:12])[CH3:13])=[CH:6][N:5]=1)([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:31]
Reactant: CC(C)(C)CC(C)(C)Nc1cc(N)c(I)cn1
Reactant: C[Si](C)(C)C#Cc1cnc(C#N)cc1N
Product: CC(C)(C)CC(C)(C)Nc1cc(N)c(C#C[Si](C)(C)C)cn1

Procedure:
The compound was prepared following the procedure same as that of 4-amino-5-[(trimethylsilyl)ethynyl]pyridine-2-carbonitrile starting from 5-iodo-N2-(2,4,4-trimethylpentan-2-yl)pyridine-2,4-diamine.
Reaction SMILES: [F:1][CH:2]([CH:6]([CH3:9])[CH2:7][CH3:8])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:13])=O>ClCCl>[F:1][CH:2]([CH:6]([CH3:9])[CH2:7][CH3:8])[C:3]([Cl:13])=[O:4]
Reactant: CCC(C)C(F)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCC(C)C(F)C(=O)Cl
Temperature: 40 °C

Procedure:
Finally, to the compound (v) was added 10 ml of dichloromethane and then 15 ml of oxalic acid chloride dropwise with ice cooling. The reaction was carried out under reflux at 40° C. for 3 hours. The reaction product was freed of chloromethane and oxalic acid chloride by atmospheric distillation, and the residues were purified by vacuum distillation. Thus there was obtained 2-fluoro-3-methylpentanoic acid chloride (vi), which has a boiling point of 58°-60° C. (at 20 mmHg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]=23)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ccnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)c(F)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a7) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH2:17][CH3:18])[C:14](O)=[O:15]>>[CH2:17]([CH:13]1[S:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11][C:14]1=[O:15])[CH3:18]
Reactant: Cc1ccccc1NC(N)=S
Reactant: CCC(Br)C(=O)O
Product: CCC1SC(Nc2ccccc2C)=NC1=O

Procedure:
Synthesis was performed from N-(2-methylphenyl)thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCC2CC2)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CCl)ccc1OCC1CC1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of (4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl)methanol (0.258 g, 1.454 mmol) in toluene (4 mL) was added thionyl chloride (0.637 mL, 8.72 mmol). The reaction was stirred at 75° C. for 1.5 h. The reaction mixture was poured into ice water and extracted with hexanes (twice). The combined extracts were washed with NaHCO3 (thrice), dried over MgSO4 and concentrated to give the title compound as a white solid (0.275 g). 1H NMR (400 MHz, CDCl3) δ ppm 0.36-0.43 (m, 2H), 0.59-0.67 (m, 2H), 1.21-1.34 (m, 1H), 3.95 (d, J=6.44 Hz, 2H), 4.56 (s, 2H), 6.95 (d, J=8.59 Hz, 1H), 7.48 (dd, J=8.53, 2.34 Hz, 1H), 7.58 (d, J=2.15 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:32])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:33]I>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:32])[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:33])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3C)CC2)c(C)c1
Reactant: CI
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC)cc3C)CC2)c(C)c1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-4-hydroxymethyloxazolidin-2-one (150 mg) described in Example 222 and methyl iodide (21 μL), (R)-3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-4-methoxymethyloxazolidin-2-one was obtained. The obtained compound was dissolved in a mixture of ethyl acetate and methanol, 4N hydrogen chloride/ethyl acetate was added, and the solvent was evaporated. To the obtained residue was added diisopropyl ether, and the mixture was filtered to give the title compound (140 mg).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:22](=O)([O-])[O-].[Cs+].[Cs+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:22][O:1][C:2]1[C:3](=[O:21])[N:4]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCC(=O)C1=C(OC)C(=O)N(Cc2ccc(OC)cc2)CC1

Procedure:
3-Hydroxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one (17.35 kg, 60 moles) and cesium carbonate (22.126 kg, 67.9 moles) were added to dry dimethylformamide (24 gal, 90.8 L) in a clean, dry 100 gallon tank. The suspension was stirred a half hour to insure dispersion. Dimethyl sulfate (8.552 kg, 67.8 moles) was added neat over a period of 30 minutes keeping the temperature 20-25° C. When the charge was complete the addition funnel was rinsed into the tank with additional DMF (500 ml). The reaction was allowed to stir at 20-25° C. for 16 hours. The reaction was diluted with ethyl acetate (108 gal, 408.8 L) and was washed with water (4×22 gal (83.3 L)). The ethyl acetate solution was washed with a solution made up of 6.94 liters 50% sodium hydroxide in 22 gal (83.3 L) of water followed by washing with a solution made up with 6.94 liters of concentrated HCl in 22 gal (83.3 L) of water. The organic solution was dried by washing with brine (14 gal, 53 L) The ethyl acetate was vacuum stripped to an oil which was suitable for use in the next step. The estimated yield based on NMR analysis of residual solvent was 89%. A small sample was isolated for characterization.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(O)[CH2:30]CC[CH2:27][CH2:26]1.[C-]#N.[K+]>>[Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:27][CH2:26][CH2:25][CH2:30][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reaction time: 24 h

Procedure:
A mixture of 9.50 g (24.3 mmol) of ethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 60 ml (560 mmol) of cyclohexanol and 300 mg of powdered potassium cyanide is stirred at 130° for 24 hours, a small amount of cyclohexanol being distilled off from time to time. The solution obtained is subsequently evaporated to dryness, the residue is taken up in chloroform, washed with water and dried over magnesium sulphate. After removal of the solvent, the residue is chromatographed on a silica gel column while eluting with ethyl acetate and subsequently recrystallized from ethyl acetate. There is obtained cyclohexyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 167°-168°.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[C:16]4[C:21]([CH:22]=[C:23]5[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:29][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[CH:27]2
Reactant: c1ccc2c(-c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2c3ccccc3cc3ccccc23)c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
9,9′-bianthracene (10 g, 28.2 mmol) was dissolved in DMF (200 mL), protected from light and N-bromosuccinimide (5.5 g, 31 mmol) diluted in DMF (20 ml) was added to the solution at 0° C. The reaction mixture was maintained at 0° C. for 1 hour. The solution was then warmed slowly to room temperature and stirred for 4 h. After the reaction completion, water was added to the mixture to terminate the reaction. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product 4.5 g (37%) as a yellow solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([O:29][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[N:35]2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid (2.22 g, 5 mmol) and 1-hydroxybenzotriazole (0.74 g, 5.5 mmol) in tetrahydrofuran (22 ml) was added N,N'-dicyclohexylcarbodiimide (1.14 g, 5.5 mmol) at 5°-10° C. and the mixture was stirred at the same temperature for 3 hours. Precipitated N,N'-dicyclohexylurea was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (20 ml) and insoluble material was removed by filtration. The chloroform was evaporated and the residue was treated with a small quantity of ether to give colorless needles of 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (2.60 g, 93%), mp 178°-179° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18].O>ClCCl>[CH2:17]([NH:19][C:20]([N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15]1)=[O:21])[CH3:18]
Reactant: COc1ccc(F)c(CC2CCNCC2)c1
Reactant: CCN=C=O
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)N1CCC(Cc2cc(OC)ccc2F)CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A magnetically stirred solution of 4-[(2-fluoro-5-methoxyphenyl)methyl]piperidine (0.895 g, 4.01 mmol) in anhydrous dichloromethane (15 mL) at 5° C. was treated dropwise with a solution of ethyl isocyanate (0.320 g, 4.41 mmol) in dry dichloromethane (5 mL). The solution was stirred 0.5 h at 5° C., allowed to warm to room temperature and stirred for 48 h. The solution was poured over ice (50g), and treated with water (200 mL) and dichloromethane (250 mL). The layers were separated, the aqueous phase was back-extracted with fresh dichloromethane (3×200 mL), and the combined organic portions were washed with 1N hydrochloric acid solution (350 mL), 5% sodium hydroxide solution (400 mL), water (400 mL), saturated brine (400 mL), dried is (K2CO3), filtered, and concentrated in vacuo. Drying (85° C.) in vacuo gave 1.08 g (92%) of the desired product as a clear oil: IR (film) 3346, 2930, 1622, 1592, 1538, 1498, 1274, 1252; 1214, 1036 cm-1 ; 1H NMR (CDCl3) δ6.90 (t, J=9.0 Hz, 1H), 6.69-6.60 (m, 2H), 4.50 (bt, J=4.7 Hz, 1H), 3.89 (bd, J=13.2 Hz, 2H), 3.74 (s, 3H), 3.27-3.17 (m, 2H), 2.67 (td, J=12.8, 2.4 Hz, 2H), 2.52 (dd, J=7.1, 1.1 Hz, 2H), 1.74-1.61 (m, 1H), 1.62 (bd, J=13.5 Hz, 2H), 1.18 (qd, J=12.0, 4.0 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3)δ57.7, 155.7 (d, J=237.1 Hz), 155.4 (d, J=1.7 Hz, 127.8 (d, J=18.0 Hz), 116.6 (d, J=5.1 Hz), 115.5 (d, J=24.7 Hz), 112.1 (d, J=8.0 Hz), 55.7, 44.1, 37.0, 36.2, 35.7, 31.7, 15.6; MS m/z 295 (M+ +1, free base).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:4][C:3]=1[C:13]([CH3:15])=[O:14].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:4][C:3]=1[C:13]([CH3:15])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1cc(OCC2CO2)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cc(OCC2CO2)ccc1OCc1ccccc1

Procedure:
A solution containing 1 g (0.0048 mole) of the product of example 39, 0.856 ml (0.00072 mole) of benzyl bromide and 0.924 g (0.0072 mole) of K2CO3 in 12 ml of acetone are heated for 6 hours under reflux in nitrogen. Then 0.5 ml (0.0042 mole) of benzyl bromide are added and the mixture heated for a further 7 hours. The substance is poured into water, extracted with ethyl acetate and the solvent evaporated off . The reaction product is purified by chromatography, eluting with an 8/2 mixture of hexane and acetone. The required product is obtained, MP: 45-48° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)[NH2:8])#[N:2].[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:11][CH2:12][C:13]([NH:8][C:7]1[CH:9]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[CH3:10])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C#N)cc1N
Product: Cc1ccc(C#N)cc1NC(=O)CCl

Procedure:
The subtitle compound was prepared from 5-cyano-2-methylaniline (1.6 g) and chloroacetyl chloride (1.1 ml) by the method of Example 33 step (iii) as a white solid. Yield: 1.85 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[NH:14][C:13]3[CH:19]=[CH:20][C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:12]=3[S:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][N:14]1[C:13]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][C:12]=2[S:11][C@@H:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C@@H:16]([OH:17])[C:15]1=[O:18]
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1F
Reactant: CN(C)CCCl
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1F

Procedure:
Following a procedure similar to that described in Example 11(d), 400 mg of (2S, 3S)-2-(3-fluoro-4-methoxyphenyl)-2,3-dihydro-3-hydroxy- 8-phenoxy-1,5-benzothiazepin-4(5H)-one [prepared as described in step (c) aboVe] were alkylated with 2-dimethylaminoethyl chloride hydrochloride to afford 500 mg of the title compound as a syrup.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=1)[CH2:13][N:14]=[N+:15]=[N-:16].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:14]([CH2:13][C:12]2[CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=[C:10]([Br:9])[CH:11]=2)[N:15]=[N:16][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [N-]=[N+]=NCc1cc(Br)cc(C(Cl)=C(Cl)Cl)c1
Reactant: N#CCC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)c1nnn(Cc2cc(Br)cc(C(Cl)=C(Cl)Cl)c2)c1N
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 36.7 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (546 mg) in 20 ml of ethanol, 6.47 ml of a methanolic solution of NaOH (1N) was added and the resulting mixture was stirred at 60° C. for 20 minutes. A solution of 3-bromo-5-(trichlorovinyl)benzyl azide (1.02 g) in 10 ml of ethanol was added and the reaction mixture heated at 60° C. for two hours. The pH of the solution was adjusted to ~6 with acetic acid and then concentrated to a small volume. Dilution with 50 ml of water afforded a precipitate which was washed thoroughly with water. The precipitate was recrystallized from 8 ml of ethanol to give 466 mg of pure product, m.p. 175°-177° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 59 %

Procedure:
Compound 2b (800 mg, 1.84 mmol) was subjected to Suzuki coupling conditions with compound 1f using the reaction conditions described in Example 1, Step G to obtain compound 2c as a yellow solid (500 mg, 59% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H21N7O: 460.2 (M+H). found: 460.3.