Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:14]=2[CH:15]=1)[CH2:8][CH2:9][CH3:10].C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl-].C[N+](C)(C)C.O>[CH2:7]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][C:14]=2[CH:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1cc2cc(N)ccc2o1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Methanesulfonyl chloride (0.92 g, 0.6 mL, 8.0 mmol) was added dropwise to a stirred boiling mixture of 2-butyl-5-benzofuranylamine hydrochloride [12a] (0.90 g, 4.0 mmol), tetramethylammonium chloride (0.11 g, 1.0 mmol) and toluene (10 mL) for 1 hour. The mixture was stirred under reflux conditions for 1 hour. Ethyl acetate (20 mL) and water (30 mL) were added to the cold mixture. The organic layer was separated and aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give 1.01 g (94.0%) of N-(2-butyl-5-benzofuranyl)methanesulfonamide [14] with mp 104.9-105.9° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([NH2:30])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:30][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[C:16]([Cl:15])[CH:17]=2)=[O:10])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: COc1cc(Br)ccc1OCC(=O)O
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(Br)cc2OC)cc1Cl

Procedure:
The product was prepared according to general working method I from 2-(4-bromo-2-methoxy-phenoxy)-acetic acid (1 32b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:18]([C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19].[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[CH2:18]([C:20]1([C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[O:35][C:2]2[CH:9]=[C:8]([CH:10]([OH:17])[C:11]3[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19]
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Reactant: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(c2cccc(Oc3cc(C(O)c4cncn4C)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile (as described in Step E above) (0.162 g, 0.700 mmol), 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (0.173 g, 0.700 mmol) and KF.Al2O3 (0.208 g) and 18-Crown-6 (0.017 g, 0.064 mmol) were dissolved in anhydrous CH3CN (7 mL) and refluxed under Ar for 24 h. The reaction was filtered, concentrated and purified using SiO2 chromatography (1-3% MeOH/CH2Cl2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([Cl:51])[C:37]=1[OH:52]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:25])[CH3:26])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:40]2[CH:41]=[C:36]([Cl:35])[C:37]([OH:52])=[C:38]([Cl:51])[CH:39]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 85.3 %

Procedure:
Following general procedure F, tert-butyl 2-{4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]phenyl}propan-2-ylcarbamate (76 mg, 0.145 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (63 mg, 0.212 mmol) to afford the crude product (75 mg) as a yellow solid: ESI MS m/z 606 [C33H33Cl2N3O4+H]+.
Reaction SMILES: C([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[C:7]([Br:17])[CH:6]=2)C.O.[OH-].[Li+]>CO.O>[Br:17][C:7]1[CH:6]=[C:5]2[C:10]([C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3][N:4]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9][CH:8]=1
Reactant: CCc1c(C(=O)O)c(=O)c2ncc(Br)cc2n1Cc1ccccc1Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2Oc2ccccc2)c2cc(Br)cnc2c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.7 %

Procedure:
To a light brown solution of ethyl 7-bromo-4-oxo-1-(2-phenoxybenzyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (22) (230 mg, 0.5 mmol) in methanol (20 mL) was added the solid lithium hydroxide monohydrate (438 mg, 10.4 mmol) at room temperature. The resulting light brown solution was stirred for 15 h at room temperature at which time LCMS analysis indicated the absence of starting material. Then, it was diluted with water and the methanol was removed under vacuum. The resulting brown paste was difficult to dissolve in 1.0N NaOH and water. Then, the neutral impurities were extracted into ethyl acetate and the basic aqueous layer was diluted with water (˜100 mL). Then, the basic aqueous solution was neutralized with 1.0N HCl. The resulting solids were collected by filtration and washed with water and hexanes. After air drying, 40 mg of 7-bromo-4-oxo-1-(2-phenoxybenzyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (23) (17% yield) was isolated as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[C:5]#[N:6].CC(C)[O-:13].[Ti+4:15].CC(C)[O-:18].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([O-:1])[C:3]=1[O-:13])#[N:6].[Ti+4:15].[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([O-:1])[C:3]=1[O-:18])#[N:6]
Reactant: CC(C)[O-]
Reactant: N#Cc1ccc(O)c(O)c1
Agent: [Ti+4]
Solvent: Cc1ccccc1
Product: N#Cc1cccc([O-])c1[O-]
Temperature: 100 °C

Procedure:
A solution of 3,4-dihydroxybenzonitrile (5.00 g, 37.0 mmol) and toluene (45 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, 5.25 g (18.5 mmol) of titanium(IV) isopropoxide (TTIP) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (3,4-dihydroxybenzonitrile-titanium complex) was brown in color. The yield amount was 5.80 g (18.5 mmol), and the yield percentage was 100%. 3.14 g of 3,4-dihydroxybenzonitrile-titanium complex was dissolved into 100 mL of ethanol to produce a coating liquid.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][OH:12].C=O>O>[OH:12][CH2:11][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: CO
Reactant: Oc1nc2ccccc2s1
Agent: C=O
Solvent: O
Product: O=c1sc2ccccc2n1CO
Temperature: 0 °C
Yield: 94 %

Procedure:
To a stirred slurry containing 30.2 g (0.2 mol) of 2-hydroxybenzothiazole and 40 ml of methyl alcohol, 32 ml of 37% aqueous formaldehyde was added in one portion. The stirred mixture was heated at 78°-80° C. (reflux) for 30 minutes. At 80° C., 60 ml of hot water was added to the stirred solution. After cooling to 0° C., the product was collected by filtration, washed with 100 ml of heptane and air-dried at 25°-30° C. The product, 3-(hydroxymethyl)-2-benzothiazolinone, mp. 101°-3° C., was obtained in 94% yield. After recrystallization from isopropyl alcohol the melting point remained unchanged.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)[CH2:5]1.C(Cl)[Cl:23]>>[ClH:23].[CH3:1][O:2][N:3]=[C:4]1[CH2:5][C@@H:6]([C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)[NH:7][CH2:8]1
Reactant: ClCCl
Reactant: CON=C1C[C@@H](c2nc(C)no2)N(C(=O)OC(C)(C)C)C1
Product: CON=C1CN[C@H](c2nc(C)no2)C1
Product: Cl
Reaction time: 0.75 h

Procedure:
A solution was made containing tert-butyl (2S,4EZ)-4-(methoxyimino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyrrolidinecarboxylate (1.26 g, 4.25 mmol) in anhydrous DCM (120 ml). At 0° C., HCl gas, previously dried with a H2SO4 cc trap, was bubbled slowly through the reaction and deprotection was monitored by TLC using cyclohexane/ethyl acetate (1/1) and stained with a pancaldi solution. After approximately 45 minutes, TLC showed no remaining starting materiel and DCM was then evaporated under vacuo without heating to avoid pyrolidine salt decomposition. More DCM (20 ml) was then added and evaporated again under vacuo to remove remaining potential HCl (2–3 times). The desired product, (3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime, hydrochloride salt, was isolated as a white solid and used without further purification and characterization
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32](N(C)CCC2C=CC=CN=2)=[O:33])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])[CH3:11]>>[CH3:22][C:19]([C:17]1[CH:16]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:33])[CH:14]=[C:13]([C:10]([CH3:9])([CH3:11])[CH3:12])[CH:18]=1)([CH3:20])[CH3:21]
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: NCc1ccccn1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)NCc2ccccn2)cc(C(C)(C)C)c1

Procedure:
Substituting 2-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(2-pyridinylmethyl)-acetamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.[NH:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1>C(O)CCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: O[C@@H]1CCNC1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Solvent: CCCCO
Product: O[C@@H]1CCN(c2ccc3ncc(-c4cc5ccccc5o4)n3n2)C1

Procedure:
150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine and 206.2 mg (1.67 mmol) (3R)-pyrrolidin-3-ol in 5.0 mL butan-1-ol were stirred 72 h at 150° C. The solvent was removed. The residue was purified by HPLC to yield 23 mg (13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH:9]=[O:10])=[CH:4][CH:3]=1.[CH3:30][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH:9]([OH:10])[CH3:30])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(C(C)O)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 1-[2-(4-chlorophenyl)-1-oxobutan-2-yl]-1H-indazol-4-ylcarbamate (2.50 g, 6.05 mmol) in anhydrous THF (50 mL) was added methylmagnesium bromide (2.5 M in ether, 7.3 mL, 18.15 mmol) at 0° C. The mixture was stirred for anther 30 min at 0° C., then saturated NH4Cl (100 mL) was added and the mixture was extracted with EA. The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to provide the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:15]#[N:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CCN(Cc2ccccc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
16.8 g (0.08 mole) (3RS)-1-benzyl-3-chloromethyl pyrrolidine and 5.88 g (0.12 mole) of sodium cyanide was dissolved in 250 ml dimethyl sulfoxide. The mixture was stirred at 60° C. for two days and at room temperature for one week. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to yield 14.7 g (92%) of the product.
Reaction SMILES: [C:1]([O:14][CH2:15][Cl:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.[K+].[Br-]>CCOCC>[Cl-:16].[C:1]([O:14][CH2:15][N+:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18]2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1CN2CCC1CC2
Reactant: CCCCCCCCCCCC(=O)OCCl
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)OC[N+]12CCC(CC1)CC2
Product: [Cl-]

Procedure:
2.49 g (0.01 mol) chloromethyl n-dodecanoate and 1.12 g (0.01 mol) quinuclidine were mixed and allowed to react together at room temperature for 48 hrs. Anhydrous ether was added to the mixture and the mixture was triturated in anydrous ether overnite. The solid was isolated by filtration under a nitrogen atmosphere and thoroughly washed with anhydrous ether. After drying in vacuo over calcium sulfate at room temperature, 2.1 g (0.006 mol), 17 was obtained as a white solid, mp 170°-172°; ir (KBr) 2960, 2930, 1765, 1470, 1120, 1090, 860 and 830 cm-1 ; pmr (CDCl3) δ 5.8 (s, 2H), 3.9 (t, 6H), 2.5 (t, 2H), 2.2 (m, 7H), 1.3 (bs, 18H) and 0.9 (t, 3H) ppm.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10]CC)=O)[CH2:4][CH2:3]1.O.[NH2:14][NH2:15]>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([NH:14][NH2:15])=[O:10])[CH2:4][CH2:3]1
Reactant: NN
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](O)CC1

Procedure:
A mixture of cis/trans ethyl 4-hydroxycyclohexane carboxylate (5.0 g, 29 mmol) and hydrazine hydrate (1.4 g, 29 mmol) was heated at reflux for 24 h. Residual water was removed by azeotropic distillation with toluene. The residue was triturated from tert-butyl methyl ether. The precipitate was collected by filtration and dried in vacuo to give the title compound as white solid in 91% yield.
Reaction SMILES: F[C@H:2]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1.N[C:27]1[S:31][C:30]([C:32]2[C:37](F)=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[N:29][C:28]=1[C:40]([NH:42][C:43]1[CH:44]=[N:45][N:46]([CH3:57])[C:47]=1[CH:48]1[CH2:54][CH2:53][C@H:52]([NH2:55])[C@H:51]([F:56])[CH2:50][O:49]1)=[O:41]>>[NH2:55][C@H:52]1[C@H:51]([F:56])[CH2:50][O:49][C@H:48]([C:47]2[N:46]([CH3:57])[N:45]=[CH:44][C:43]=2[NH:42][C:40]([C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH3:2])=[CH:34][C:33]=3[F:39])[S:31][CH:27]=2)=[O:41])[CH2:54][CH2:53]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@H](N)[C@H](F)CO1
Product: Cc1ccc(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c(F)c1

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-fluoro-4-methylphenyl)thiazole-4-carboxylic acid (Intermediate 131) gave 316. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.48 (s, 1H), 8.36 (t, J=8.1 Hz, 1H), 7.89 (s, 1H), 7.34-7.18 (m, 2H), 4.87 (dd, J=10.6, 3.6 Hz, 1H), 4.57-4.39 (m, 1H), 4.38-4.25 (m, 1H), 4.19-4.01 (m, 1H), 3.78 (s, 3H), 2.40 (s, 3H), 2.12-2.03 (m, 1H), 1.88-1.78 (m, 1H), 1.77-1.66 (m, 3H). LCMS (ES+) m/z 448 (M+1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.[Si:26]([O:33][CH:34]1[CH2:45][C:44](=[O:46])[O:43][C@H:42](/[C:47](/[CH3:51])=[CH:48]/[CH2:49][OH:50])[C@@H:41]([CH3:52])[CH:40]=[CH:39][C@@H:38]2[O:53][C@H:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:55][C@:37]2([CH3:62])[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CCOCC>[Si:26]([O:33][CH:34]1[CH2:45][C:44](=[O:46])[O:43][C@H:42](/[C:47](/[CH3:51])=[CH:48]/[CH:49]=[O:50])[C@@H:41]([CH3:52])[CH:40]=[CH:39][C@@H:38]2[O:53][C@H:54]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[O:55][C@:37]2([CH3:62])[CH2:36][CH2:35]1)([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27]
Reactant: C/C(=C\CO)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Agent: C/C(=C\C=O)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: C/C(=C\CO)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(=C\C=O)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dess-Martin reagent (565 mg, 1.33 mmol) was added to a dichloromethane (12.0 ml) solution of (2S,3aS,4E,6S,7S,13aR)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1E)-3-hydroxy-1-methylprop-1-en-1-yl}-6,13a-dimethyl-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxolo[4,5-f]oxacyclododecin-9-one (587 mg, 1.11 mmol). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ether and washed with a saturated sodium hydrogen carbonate aqueous solution containing sodium sulfite, water and brine sequentially and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=10:1→8:1→6:1) to obtain the title compound (587 mg) as a white solid. This was obtained as a colorless crystal by recrystallization (hexane:ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:36])=[C:17]([C@@:19]23[O:27][CH2:26][CH2:25][C@@H:24]2[CH2:23][S:22][C:21]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20]3)[CH:18]=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>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([F:36])=[C:17]([C@@:19]34[O:27][CH2:26][CH2:25][C@@H:24]3[CH2:23][S:22][C:21]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[N:20]4)[CH:18]=2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC(=O)c4ccc(C#N)cn4)ccc3F)OCC[C@@H]2CS1
Yield: 40 %

Procedure:
A solution of 5-cyanopicolinic acid (6.65 mg, 0.045 mmol), tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (11 mg, 0.030 mmol), HATU (17.07 mg, 0.045 mmol) and Hunig's Base (10.46 μL, 0.060 mmol) in DMF (299 μL) was stirred at rt for 12 h. The crude product was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(5-(5-cyanopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol, 40.3% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.90 (s, 1H), 8.94 (d, J=1.2 Hz, 1H), 8.45 (d, J=8.1 Hz, 1H), 8.24 (dd, J=8.1, 2.0 Hz, 1H), 8.10-7.97 (m, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.16 (dd, J=10.7, 9.0 Hz, 1H), 4.27-4.06 (m, 2H), 3.32 (d, J=12.7 Hz, 1H), 3.04-2.84 (m, 2H), 2.49-2.34 (m, 1H), 2.23 (td, J=13.0, 7.9 Hz, 1H), 1.51 (s, 9H). MS (M+H)+: 498.20.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH:1]([N:4]([P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])Cl)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][CH:25]([OH:27])[CH3:26]>C(OCC)C>[CH:25]([O:27][P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:26])[CH3:24]
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Reactant: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)OP(N(C(C)C)C(C)C)N(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Bis(diisopropylamino)chlorophosphine (19, 250.1 g, 937 mmol) was dissolved in anhydrous ethyl ether (3.6 L) and triethylamine (190 g, 1.87 mol) was introduced. The turbid mixture was cooled at 0° C. and a solution of 2-propanol (225 g, 287 mL) in ether (200 mL) was added via a funnel. The resulting cloudy mixture was stirred at room temperature for 5.5 hours. The reaction was complete by checking with 31P NMR (δ=116.10 ppm, S). White solid (triethylamine HCl salt) was removed by filtration. The filtrate was concentrated to furnish a pale brown liquid (272 g, quantitative) and used for next step without further purification. Note that the P(III)-reagent can be purified by vacuum distillation (bp 84-86° C., 5 mm Hg) if desired to furnish a colorless clear oil. 1H NMR (CDCl3): δ 3.91 (m, 1H), 3.51 (m, 4H), 1.19 (d, 6H, J=6 Hz), 1.16 (24H, m). 31P NMR (CDCl3): δ 116.1.