Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][S:43](CN1C=CC(N)=N1)(=[O:45])=[O:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][S:43]([CH3:42])(=[O:45])=[O:44])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (166 μL, 0.33 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (46 μL, 0.39 mmol) was added to the solution at 0° C. After 1 h, 1-methanesulfonylmethyl-1H-pyrazol-3-ylamine (0.30 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-methanesulfonylmethyl-1H-pyrazol-3-yl)-propionamide (133 mg, 90%) as a white solid: ESI-LRMS m/e calcd for C20H26ClN3O5S2 [M+] 487.1, found 488.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.22 (m, 2H, CH2), 1.43-1.94 (m, 8H, 4×CH2), 2.09-2.29 (m, 1H, CH), 2.86 (s, 3H, SO2CH3), 3.27 (s, 3H, SO2CH3), 3.58 (t, J=7.5 Hz, 1H, CH), 5.25 (s, 2H, NCH2), 6.87 (d, J=2.5 Hz, 1H, Ar), 7.48 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.54 (d, J=2.5 Hz, 1H, Ar), 7.61 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.1 Hz, 1H, Ar), 8.10 (brs, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(Cc2ccccc2)c(-c2ccccc2)s1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nc(Cc2ccccc2)c(-c2ccccc2)s1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as the raw materials, the same operation as the example 195(3) gave the title compound. (2-Amino-4-benzyl-5-phenylthiazole: refer to Chem. Pharm. Bull., 1962, 10, 376.)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:15]O.N1C=CC=CC=1>CCOCC>[Cl:3][CH2:15][C:8]1[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(CCl)c(OC)c1
Temperature: 0 °C

Procedure:
Thionyl chloride (116 mL, 1586 mmol) was added dropwise over 1 hour to a turbid solution of (2,4-dimethoxyphenyl)methanol (97.00 g, 577 mmol) and pyridine (93 mL, 1153 mmol) in anhydrous Et2O (1153 mL) at 0° C. under nitrogen with mechanical stirring. After 1 hour the reaction mixture was poured into 2 L of ice water and the layers were separated. The aqueous layer was extracted with Et2O (2×1 L) and the organics were pooled, washed with ice water (1.2 L), cold 5:1 sat. aq. NaCl solution/sat. aq. NaHCO3 (1.2 L), dried (MgSO4), filtered and most of the ether was removed in vacuo at 12° C. Benzene (300 mL) was added and the mixture was concentrated at 12° C. until 100 mL of benzene remained to provide a solution of 1-(chloromethyl)-2,4-dimethoxybenzene.
Reaction SMILES: [Li]CCCC.CCCCC.[C:11]([Si:15]([CH3:27])([CH3:26])[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)([CH3:14])([CH3:13])[CH3:12].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].[Br:36]N1C(=O)CCC1=O>C1COCC1.C(OCC)C>[Br:36][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([O:16][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:27])[CH3:26])[CH:18]=2)[N:22]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(Br)cn2[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A 1.6 M solution of BuLi in pentane (30.7 ml, 49.2 mmol) was added to a solution of 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole (9.36 g, 37.8 mmol) in THF (190 ml) at −78° C. within 20 min under an argon atmosphere. The reaction mixture was stirred for 20 min at −78° C. tert-Butyldimethylsilyl chloride (7.64 g, 49.2 mmol) was added and the reaction mixture was stirred for 10 min at −78° C. and for 1 h at RT. The mixture was chilled to −78° C., N-bromosuccinimide (7.64 g, 41.6 mmol) was added and the solution was stirred for 1 h at −78° C. and for 1 h at RT. Diethyl ether was added and the mixture was washed with saturated aqueous NaHCO3 solution and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, CH2Cl2/heptane 1:19) to give 12.87 g (29.2 mmol, 77%) 3-bromo-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:10]1([C:9]2[NH:1][C:2]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:9]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccnc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cccnc1NC(=O)c1ccccc1
Product: c1ccc(-c2cc3cccnc3[nH]2)cc1

Procedure:
2-phenyl-7-azaindole was prepared in two steps. First, 2-amino-3-picoline was reacted with benzoyl chloride in chloroform in the presence of pyridine to produce 2-benzamido-3-picoline in 33% yield. Second, pyrolysis of 2-benzamido-3-picoline in N-methylaniline in the presence of NaH at 280° C. was performed to produce 2-phenyl-7-azaindole (FIG. 18) in 58% yield. This compound was characterized by NMR spectroscopy.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:11][CH2:12][CH2:13][OH:14])(=[O:10])C=C.[CH2:15]1COC[CH2:16]1>>[CH:2]12[CH2:16][CH2:15][CH:5]([CH:6]=[CH:1]1)[CH2:4][CH:3]2[C:7]([O:11][CH2:12][CH2:13][OH:14])=[O:10]
Reactant: C=CC(=O)OCCO
Reactant: C1=CCCC=C1
Reactant: C1CCOC1
Product: O=C(OCCO)C1CC2C=CC1CC2
Reaction time: 24 h
Yield: 51 %

Procedure:
Cyclohexadiene (80 g) and 140 g of 2-hydroxyethyl acrylate were dissolved in 500 g of THF solvent. After reacting at 50° C. for 24 hours, the solvent was removed by rotary evaporator. The residue was distilled under reduced pressure to obtain 100 g of 2-hydroxyethyl bicyclo[2,2,2]oct-5-ene-2- carboxylate as a mixture of endo and exo (yield: 45%).
Reaction SMILES: [CH2:1]([C:4]1[N:13]=[C:12]([S:14][CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].[CH3:16][I:17]>>[I-:17].[CH3:16][N+:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([S:14][CH3:15])=[N:13][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CI
Reactant: CCCc1nc(SC)c2ccccc2n1
Product: CCCc1nc(SC)c2ccccc2[n+]1C
Product: [I-]

Procedure:
A solution of 2-propyl-4-methylthioquinazoline (1.08 g.) in methyl iodide (5 ml.) was heated under reflux for 18 hours. The solid was separated from the cooled mixture and washed with ether to give 1-methyl-4-methylthio-2-propylquinazolinium iodide; n.m.r. in d6DMSO:-1.15(t, 3H); 2.0(m, 2H); 2.9(s, 3H); 3.35(t, 2H); 4.3(s, 3H); 7.9-8.6(complex, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C([O-])([O-])=O.[K+].[K+].I[CH:57]([CH3:59])[CH3:58]>CC#N>[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:57]([CH3:59])[CH3:58])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 95 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
Benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (2.3 g, 3.43 mmol) was mixed with K2CO3 (3.3 g, 24 mmol) and 2-iodopropane (5.8 g, 34.3 mmol) in MeCN (25 mL) in a sealed tube, then heated to 95° C. with stirring for 20 h. The reaction mixture was filtered and rinsed with MeCN (30 mL), the filtrate was evaporated in vacuo to afford the desired compound (2.1 g, yield: 88%) as a white solid, which was used for next step without further purification. 1H NMR (500 MHz, MeOD): δH 8.13 (s, 1H), 7.35-7.29 (m, 5H), 7.18 (d, J=3.0 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.64 (d, J=3.0 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 6.41 (dd, J=8.5 and 2.5 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 5.33-5.32 (m, 1H), 5.08-5.06 (m, 2H), 4.90-4.89 (m, 1H), 4.64 (s, 2H), 4.15-4.14 (m, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.37-3.36 (m, 0.43H), 3.01-2.98 (m, 0.59H), 2.92-2.88 (m, 1H), 2.70-2.40 (m, 3H), 2.24-2.18 (m, 2H), 2.10-1.80 (m, 3H), 1.75-1.69 (m, 2H), 1.61-1.52 (m, 5H), 1.38 (s, 3H), 0.94 (d, J=6.5 Hz, 3H), 0.81-0.79 (m, 3H) ppm; LC-MS (m/z): 714.0 [M+1]+.
Reaction SMILES: [O:1]([CH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[O:1]([CH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)nn1
Yield: 61.4 %

Procedure:
A suspension solution of methyl 6-(1-phenoxyethyl)pyridazine-3-carboxylate (0.1 g, 0.4 mmol) and lithium hydroxide (48 mg, 2 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was stirred at room temperature for 2 hours. The mixture solution was diluting with ethyl acetate (50 mL), and acidified with hydrochloric acid to PH<5. The organic layer was separated, dried over sodium sulfate, and concentrated to give 6-(1-phenoxyethyl)pyridazine-3-carboxylic acid (60 mg, 65%) which was used directly for the next step without purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:1]([CH3:2])=[N:4][CH2:5][CH2:6]2
Reactant: COc1cccc(CCNC(C)=O)c1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a stirred solution of N-acetyl-3-methoxyphenethylamine (96.0 g, 0.497 m) in toluene (600 ml) at 15°-20° C. phosphorus oxychloride (190.5 g, 1.24 m) was added dropwise over 2 hours. The reaction was stirred overnight at room temperature, then poured into 1 liter of ice water. The organic layer was washed with dilute HCl (2×300 ml), and the aqueous layers were combined, basified, and extracted with CHCl3 (2×500 ml). The dried chloroform layer (MgSO4) was concentrated to an oil. The oil was dissolved in ether and acidified with HCl gas to yield 55.9 g of the product, 3,4-dihydro-6-methoxy-1-methylisoquinoline, m.p. 206°-207°.
Reaction SMILES: CI.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:19]([O-])(O)=O.[Na+].O>CN(C=O)C>[CH3:19][O:16][C:15](=[O:17])[CH:14]([OH:18])[CH2:13][CH2:12][CH2:11][NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)NCCCC(O)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Yield: 42.4 %

Procedure:
A solution of methyl iodide (11.5 mL, 0.189 mol) in DMF (50 mL) was added dropwise during 15 min. to a mixture of 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid (22.0 g, 94.4 mmol) and NaHCO3 (11.8 g, 141 mmol) in DMF (150 mL). After stirring over night, water was added and the mixture was extracted with ethyl acetate. The pooled organic phases were washed with water and brine, dried and concentrated under reduced pressure. The crude product was purified using chromathography (heptane/ethyl acetate, 1:1) to give 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester 9.9 g, 42.5%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[N:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:28][CH:27]=2)[CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.44 (d, 2H), 7.32 (d, 2H), 7.24 (m, 2H), 7.17 (m, 3H), 7.07 (d, 1H), 3.82 (s, 2H), 3.77 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.61 (t, 2H); MS 350 (M+1).
Reaction SMILES: [F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[O:5]
Reactant: COc1cccc(C(=O)N(C)OC)c1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a solution of 2-fluoro-3,N-dimethoxy-N-methyl-benzamide (2.30 g, 10.8 mmol) in THF (20 mL) at −78° C. was added 1M DIBAL-H in toluene (12 mL, 12 mmol). The reaction stirred at −78° C. for 3 h and then the remaining 1M DIBAL-H in toluene (4.2 mL, 4.2 mmol) was added to the reaction. The reaction was allowed to stir at −78° C. for 30 min and was then warmed to rt. The reaction was quenched slowly with saturated aqueous NH4Cl. The organic phase was separated and the aqueous phase was extracted with 2×50 mL ethyl acetate. The combined organic phases were washed successively with 1N HCl and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:1] to yield the title compound (1.41 g, 85%): δH (300 MHz, CDCl3): 10.38 (1H, s), 7.43-7.40 (1H, m), 7.24-7.15 (2H, m), 3.95 (3H, s).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:34]1[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:39]([C:37]2[N:38]=[C:34]([C:28]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=3[F:26])[S:35][CH:36]=2)=[O:40])[CH2:6][CH2:7]1
Reactant: O=C(O)c1csc(-c2ccc(F)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3ccc(F)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,4-difluorophenyl)thiazole-4-carboxylic acid (see US2008/76771) gave 325. 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.56-8.46 (m, 2H), 7.88 (s, 1H), 7.59-7.50 (m, 1H), 7.32-7.24 (m, 1H), 4.87 (dd, J=10.4, 3.5 Hz, 1H), 4.57-4.38 (m, 1H), 4.38-4.23 (m, 1H), 4.18-3.98 (m, 1H), 3.78 (s, 3H), 2.14-2.02 (m, 1H), 1.88-1.66 (m, 4H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16]O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([O:34][C:35]([NH:37][S:38]([NH:41][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=[O:40])=[O:39])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:30]([O:34][C:35]([N:37]([CH2:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1)[S:38]([NH:41][CH2:42][CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)(=[O:40])=[O:39])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCC1CCCCC1
Reactant: OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)S(=O)(=O)NCC1CCCCC1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of the product from step d (764 mg, 2.00 mmol), the product from step e (642 mg, 2.20 mmol) and triphenylphosphine 576 mg, 2.20 mmol) in dry tetrahydrofuran (20 ml), under an atmosphere of argon, was added over 10 min a solution of diethylazodicarboxylate (383 mg, 2.20 mmol) in dry tetrahydrofuran (5 ml). The mixture was stirred for 2 h, the solvent evaporated and the residue purified by flash column chromatography (silica; 30% ethyl acetate/dichloromethane). Thus, the product was isolated as a colourless foam (800 mg, 60%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[SH:9][C:10]1[NH:11][C:12]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[N:15]=[CH:14][C:13]=2[N:30]=1>ClCCl.CO>[CH3:1][S:9][C:10]1[NH:11][C:12]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[N:15]=[CH:14][C:13]=2[N:30]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c2[nH]c(S)nc2cnn1Cc1cccc2ccccc12
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CI
Product: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.38 g (17.2 mmol) of potassium carbonate and 1.07 ml (17.20 mmol) of iodomethane were added to a suspension of 5.3 g (17.19 mmol) of 2-mercapto-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 100 ml of dichloromethane and 100 ml of methanol and stirred overnight at ambient temperature. Then the solvent was evaporated off, the residue was combined with approx. 30 ml of water, acidified with 2N hydrochloric acid, the product thus obtained was suction filtered, washed again with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][OH:27])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P(CCCC)(CCCC)CCCC>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccccc1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCO)C2)CC1
Agent: CCCCP(CCCC)CCCC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCOc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
N-(3,4-Dichlorophenyl)-4-{[(3S)-1-(2-hydroxyethyl)piperidin-3-yl]methyl}piperazine-1-carboxamide (250 mg, 0.62 mmols) and phenol (58.35 mg, 0.62 mmols) were stirred at room temperature under an atmosphere of argon before addition of P(Bu)3 (0.30 ml, 1.24 mmols) and 1,1-azodicarbonyl dipiperidine (312 mg, 1.24 mmols). This reaction mixture was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was washed using brine and the organic layer dried (MgSO4) filtered then concentrated in vacuo onto silica gel (1 g). The resulting solid was subjected to chromatography on silica gel (20 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (65.4 mg).
Reaction SMILES: C[Si](C)(C)C1C=C(CC(O)([P:17](=[O:22])([O:20]C)[O:18]C)[P:11](=[O:16])([O:14]C)[O:12]C)C=CC=1.P([O-])(OCC)[O:27]CC.[Na+]>C1COCC1>[PH:11](=[O:12])([OH:16])[OH:14].[P:17]([OH:20])([OH:27])([OH:18])=[O:22]
Reactant: COP(=O)(OC)C(O)(Cc1cccc([Si](C)(C)C)c1)P(=O)(OC)OC
Reactant: CCOP([O-])OCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=P(O)(O)O
Product: O=[PH](O)O
Reaction time: 2 h
Yield: 89 %

Procedure:
From 17: To a solution of the phosphonate 17 (0.289 g, 1 mmol) in THF (10 ml) was added diethyl chlorophosphate (0.259 g, 1.5 mmol) and Et3N (0.30 g, 3.0 mmol) at 0° C., After 20 min the cooling bath was removed and the reaction mixture was stirred for 48 h. The mixture was extracted with CH2Cl2, the organic phase was washed with water, 10% H3PO4, then brine and dried (MgSO4). Filtration and evaporation afforded 0.25 g (59%) of a pale yellow colored liquid. From 18: Sodium diethyl phosphite (18 mmol) was added to a solution of the phosphonate 18 (5.51 g, 15 mmol) in THF (60 ml) at 0° C., After 2 h the reaction was quenched by addition of saturated NH4Cl (aq) (1.5 ml) and the mixture was concentrated under reduced pressure. The residue was extracted with CH2Cl2, the organic phase was washed with water, then brine and dried (MgSO4). Filtration and evaporation yielded the crude product (6.45 g), which was purified by flash chromatography (silica, AcOEt/MeOH gradient) to give 4.64 g (73%) of the phosphate phosphonate 19. From 22a: Sodium diethyl phosphite (3.5 mmol) was added to a solution of the phosphonate 22a (0.91 g, 2 mmol) in THF (10 ml) at 0° C., The resulting orange mixture was stirred for 2 h and quenched by addition of saturated NH4Cl (aq) (1 ml). The product mixture was extracted with CH2Cl2, the organic phase was washed with water, then brine and dried (MgSO4). Filtration and evaporation gave 0.76 g (89%) of 19 as a yellow colored liquid. IR (film): 2910, 1535, 1350, 1290 and 1025; 1H NMR (200 MHz, CDCl3): δ1.23 (12H, m), 3.99 (8H, m), 5.64 (1H, dd, J=3, 11 Hz) and 7.87 (4H, m); 13C NMR (50 MHz, CDCl3): δ16.6 (m), 64.5 (m), 71.9 (d, J=7 Hz), 75.3 (d, J=7 Hz), 122.5, 123.8, 128.4, 129.5, 133.7 and 148.3; HR-MS (EI): m/e 425.1010 (M+C15H25NO9P2 requires 425.1006).