Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Mg].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.S(=O)(=O)(O)O.[CH2:20]([Mg:23][Br:24])[CH:21]=[CH2:22]>O1CCCC1.CCOCC>[CH2:20]([Mg:23][Br:24])[CH:21]=[CH2:22].[OH:10][C:8]([C:7]([F:6])([F:13])[F:14])([CH2:22][CH:21]=[CH2:20])[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCOC(=O)C(F)(F)F
Agent: C=CC[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)(CC=C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Allylmagnesium bromide was prepared from 140 g (1.16 mole) of allyl bromide, 35 g (1.44 mole) of magnesium and 640 ml of ether. The product was titrated and found to be 1.2 molar in allylmagnesium bromide. To a 230 ml (0.276 mole) aliquot of the reagent was added 17.4 g (0.122 mole) of ethyl trifluoroacetate in 60 ml of dry tetrahydrofuran at a drop rate of 2-3 drops/second. The reaction temperature was held near -40° during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was heated at reflux for two hours, then stirred for an additional 24 hours. The reaction mixture was poured into 300 ml of ice and 20% sulfuric acid was added to bring the pH to about 1. The phases were separated and the aqueous phase extracted with 3×70 ml of ether. The combined organic phases were dried over magnesium sulfate, filtered and the solvent evaporated. The liquid product was distilled in vacuo to give 15.2 g (70%) of 4-hydroxy-4-trifluoromethyl-1,6-heptadiene, bp 54.5-58.5° C./30 torr.
Reaction SMILES: [CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>[Cu]I>[CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:12])[N:10]([C:29]2[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCCCC1(CCCC)CSc2cc(OC)ccc2NC1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC1(CCCC)CSc2cc(OC)ccc2N(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 200 °C
Yield: 64 %

Procedure:
To 3,3-dibutyl-4-oxo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesised by the procedure of WO9616051 for the corresponding 3-butyl-3-ethyl analogue; 2.9 g, 9.0 mmol) was added p-nitrophenylbromide (24 g, 119 mmol), K2CO3 (1.6 g, 12 mmol) and CuI (180 mg, 0.95 mmol). The reaction mixture was heated to 200° C. overnight. Then it was allowed to cool down to room temperature and the resulting solid was purified by chromatography using DCM as eluent. The fractions containing the product were concentrated under reduced pressure and EtOH (95%) was added and the insoluble p-nitrophenylbromide was then filtered off. The residue was purified again by flash chromatography using DCM as eluent. The product was still not pure so the residue was then purified by flash chromatography using EtOAc:heptane, 1:9 as eluent to give the title compound 2.57 g (64%). NMR (600 MHz) 0.77–0.87 (m, 6H), 1.12–1.31 (m, 8H), 1.4–1.6 (m, 4H), 3.09 (brs, 2H), 3.79 (s, 3H), 6.72–6.83 (m, 2H), 7.18–7.27 (m, 3H), 8.3 (d, 2H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[C:6](OC)([O:8]C)[CH3:7].Cl.[CH2:15]([NH:17][C:18]([NH2:20])=[NH:19])[CH3:16].[O-]CC.[Na+]>>[CH2:15]([NH:17][C:18]1[N:20]=[C:5]([C:6](=[O:8])[CH3:7])[CH:4]=[CH:3][N:19]=1)[CH3:16]
Reactant: CCNC(=N)N
Reactant: COC(C)(OC)C(=O)C=CN(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCNc1nccc(C(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6 g of 1-dimethylamino-4,4-dimethoxypent-1-en-3-one, 3.96 g of N-ethylguanidine hydrochloride and 26 ml of 20% strength ethanolic sodium ethoxide solution is heated under reflux for 2 hours. After cooling, the solid is filtered off with suction, and the filtrate is concentrated in vacuo and mixed with 20 ml of trifluoroacetic acid and 2 ml of water and stirred at room temperature overnight. Then 50 ml of water are added, the pH is adjusted to 10 with sodium carbonate, and the mixture is extracted twice with 25 ml of ethyl acetate each time. The organic phase is dried over sodium sulfate and concentrated. The resulting oily residue is purified by column chromatography (silica gel, mobile phase: methylene chloride:methanol=98:2).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:16][CH2:17][CH:18]=C)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C(NCCC=C)=CC=CN=1.CC([O:36]C(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[O:36]=[C:18]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][N:3]=2)[N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CCCN(C(=O)OC(C)(C)C)c1cccnc1Br
Agent: C=CCCNc1cccnc1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
tert-butyl (2-bromopyridin-3-yl)(but-3-en-1-yl)carbamate. To a solution of 2-bromo-N-(but-3-en-1-yl)pyridin-3-amine (1 eq.) and DCM (0.2 M) is added (Boc)2O (1.5 eq.). The solution is stirred at room temperature until judged complete by TLC. The solution is concentrated in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([C:31]3[NH:35][C:34]4[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=4[N:32]=3)[O:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(O)C=CC=CC=1.Cl[Si](C)(C)C>ClCCCl>[CH3:30][N:27]1[CH2:26][CH2:25][CH:24]([O:23][CH:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]#[C:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:17]=2)[C:31]2[NH:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:29][CH2:28]1
Reactant: CN1CCC(OC(c2cccc(C#CC3CCN(C(=O)OC(C)(C)C)CC3)c2)c2nc3ccccc3[nH]2)CC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Solvent: Oc1ccccc1
Product: CN1CCC(OC(c2cccc(C#CC3CCNCC3)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 100 °C

Procedure:
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylethynyl}piperidine-1-carboxylic acid tert-butyl ester (160 mg) in 1,2-dichloroethane (10 mL) are added phenol (940 mg) and chlorotrimethylsilane (1.26 mL). The reaction mixture is heated to 100° C. for 30 minutes. Volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 85/15/1.5) to afford 2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])c(C)c1

Procedure:
The product was prepared by the alkylation of 4-nitro-3-methylphenol (15.3 g) with ethyl bromoacetate (16.7 g) in DMF (150 mL) in the presence of potassium carbonate (13.8 g) to afford ethyl 4-nitro-3-methylphenoxyacetate; hydrogenation of the latter (7.18 g, 0.03 mol) in ethanol (250 mL) in the presence of 5% palladium on carbon (2.1 g) to afford 6.20 g (99%) of ethyl 4-amino-3-methylphenoxyacetate as a brown oil; and treatment of the latter (6.2 g, 0.0296 mol) in CH2Cl2 (100 mL) with pyridine (10 mL), followed by methanesulfonylchloride (3.73 g, 0.033 mol) to afford 6.54 g (76.9%) of N-[4-(ethoxycarbonylmethoxy)-2-(methyl)phenyl]methanesulfonamide, m.p. 93°-94 ° C., after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:7])=[CH:4][C:3]=1[O:25][CH3:26].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:7])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NCC2CCNCC2)ccc1Cl

Procedure:
A solution of the compound prepared in Example 10 (1.44 g) in dichloromethane (8.04 mL)-trifluoroacetic acid (1.46 mL) was stirred for 18 hours. The reaction was concentrated and the excess trifluoroacetic acid was removed via azeotropic distillation from toluene and diethyl ether. The resulting oil solidified upon treatment with (diethyl ether:hexane=5:1) and the solids were collected by filtration to obtain the title compound (1.36 g) having the following physical data.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(C#N)cc1-c1nc(-c2ccccn2)no1
Temperature: 80 °C
Yield: 12 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), zinc cyanide (35.1 mg, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 23.1 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was heated under an argon atmosphere at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 30% ethyl acetate in hexane afforded 6.9 mg (12%) of 3-(2-pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-:18])(=O)=O)=CC=1.[C:20]([O:25][CH3:26])(=[O:24])/[CH:21]=[CH:22]/[CH3:23].O>O1CCCC1>[CH3:23][C:22]1[C:21]([C:20]([O:25][CH3:26])=[O:24])=[CH:16][NH:17][CH:18]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To a suspension of potassium tert-butoxide (76.7 g) in tetrahydrofuran (900 mL) was added dropwise a solution of p-toluenesulfonylmethyl isocyanide (94.6 g) and methyl crotonate (48.5 g) in tetrahydrofuran (900 mL) over 30 min. The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a white solid (yield 16.8 g, 25%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][S:12][C:13]#[N:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:16].[OH-].[Na+].O>C(O)(=O)C>[Br:16][C:13]1[S:12][CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:14]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2csc(Br)n2)cc1
Yield: 45 %

Procedure:
2-(4-Nitrophenyl)-2-oxoethyl thiocyanate (3.0 g; 15.4 mmol) and 50 mL of 30% HBr in acetic acid were stirred at room temperature under nitrogen overnight. The yellow paste was neutralized with 60 mL of 2N NaOH and 60 mL of H2O. The residue was collected by suction filtration. Purification of the residue on silica gel using a stepwise gradient of 5-50% ethyl acetate:hexane gave 2-bromo-4-(4-nitrophenyl)-1,3-thiazole (2.0 g, 45%), MS (ES) m/z 286[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:13][CH2:14]Cl)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[C:29]([OH:38])(=[O:37])[CH:30]([CH:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>CO>[C:34]([CH:32]([CH:30]([C:29]([OH:38])=[O:37])[OH:31])[OH:33])([OH:36])=[O:35].[NH2:1][C:2]1[S:3][C:4]([CH2:13][CH2:14][N:25]2[CH2:24][CH:23]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: Nc1nc(-c2ccccc2)c(CCCl)s1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccccc2)c(CCN2CC=C(c3ccccc3)CC2)s1
Temperature: 120 °C

Procedure:
20 mmol of 2-amino-5-(2-chloroethyl)-4-phenylthiazole and 20 mmol of 4-phenyl-1,2,3,6-tetrahydropyridine were thoroughly mixed and were heated under an N2 atmosphere at 120° C. until conversion was complete, which was the case after 20 minutes. After cooling, the solidified melt was stirred with water, the oily solid residue was separated off and stirred thoroughly with methanol and the solid was filtered off under suction. The filter residue was partitioned in 2 N NaOH/CH2Cl2 and the organic phase was separated off, dried and evaporated down. The residue was dissolved in methanol while hot, one equivalent of tartaric acid was added and the precipitated solid was filtered off under suction and purified by recrystallization from ethyl acetate.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1N[N:9]=[CH:8]2.BrC1C=C2C([CH:22]=[C:23]([O:28][CH3:29])N=C2)=CC=1>>[CH3:29][O:28][C:23]1[N:9]=[CH:8][C:7]2[C:11]([CH:22]=1)=[CH:3][CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=2
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Reactant: COc1cc2ccc(Br)cc2cn1
Product: COc1cc2ccc(C(=O)O)cc2cn1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 7-bromo-3-methoxyisoquinoline. +ESI (M+H) 204.2; 1H NMR (400 MHz, CD3OD, δ): 9.08 (s, 1H), 8.71 (s, 1H), 8.14 (dd, J=8.78, 1.56 Hz, 1H), 7.83 (d, J=8.78 Hz, 1H), 7.17 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][NH:24][C:25](=[S:28])[NH:26][NH2:27].[C:29]1([C:39](O)=O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>CN(C)C=O.C(N(CC)CC)C>[C:29]1([C:39]2[N:24]([CH3:23])[C:25]([SH:28])=[N:26][N:27]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CNC(=S)NN
Reactant: O=C(O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(S)nnc1-c1nccc2ccccc12
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Hydroxybenzotriazole (0.078 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g) and triethylamine were added successively to a cooled solution (0° C.) of 4-methyl-3-thiosemicarbazide (0.061 g) and 1-isoquinoline carboxylic acid (0.10 g) in dimethylformamide (3 ml). Following addition the cooling bath was removed and the mixture was stirred at room temperature over night and then the reaction mixture was evaporated to dryness. To the residue was added sodium hydroxide solution (0.5 M, 5 ml) and the mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and the pH adjusted to pH 6 using hydrochloric acid solution (2M) and the resulting precipitate was filtered and dried in vacuo to give the title compound (0.11 g, 78%) as an off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:26][OH:27])[N:13](C(OC(C)(C)C)=O)[CH2:14]2>ClCCl>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:26][OH:27])[NH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)N1Cc2cccc(Br)c2C[C@@H]1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1Cc2c(Br)cccc2CN1
Reaction time: 0.5 h

Procedure:
Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to solution of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g, 45.3 mmol) in dichloromethane (226 mL) at room temperature. Stir 30 min and concentrate under reduced pressure. Dry under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 mL). Add 1H-imidazole (51.3 g, 753 mmol), N,N-Dimethyl-4-pyridinamine (460 mg, 3.77 mmol), and t-butyldimethylchlorosilane (13.6 g, 90.4 mmol). Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 19.4 mmol of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (14.3 g, 40.1 mmol). MS (m/z): 356 (M+1).
Reaction SMILES: [NH3:1].CO.Cl[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])=[O:6]>C1COCC1>[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])(=[O:6])[NH2:1]
Reactant: O=S(=O)(Cl)c1ncn2ccsc12
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 2 M ammonia/methanol solution (4 ml) was added to a solution of 0.44 g of 7-chlorosulfonylimidazo[5,1-b]thiazole in 10 ml of THF. The mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 0.34 g of 7-sulfamoylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][Si:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:78]([O:83][CH2:84][CH3:85])(=[O:82])[C@H:79]([CH3:81])O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:44][Si:2]([CH3:43])([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41][CH:79]([C:78]([O:83][CH2:84][CH3:85])=[O:82])[CH3:81])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24]
Reactant: CCOC(=O)[C@H](C)O
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)OP(=O)(CC=CCC(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(=O)OCC[Si](C)(C)C)OC
Yield: 74.1 %

Procedure:
A solution of 2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol), PyBOP (234 mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate (53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperature for 1 hour when complete consumption of the starting materials was observed. The reaction was worked up by addition of saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated and washed with 5% aqueous solution of lithium chloride. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (0-20%) to provide 57 mg (74%) of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7 Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz), 3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9 Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61 (m, 2H); 31P (121.4 MHz, CDCl3) δ 28.9, 29.9; MS (m/z) 791.4 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(5-methylthiophene-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate u) (example 9, step a) (0.32 g) in DCM (3 mL) was treated with trifluoroacetic acid (1.0 g). After 2 h, the reaction mixture was evaporated in vacuo and azeotroped twice with toluene to yield the subtitled compound which was used directly. Yield 0.32 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([C:35]([F:38])([F:37])[F:36])[CH2:32][C@H:31]([NH:39]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=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>[NH2:39][C@H:31]1[CH2:32][C@@H:33]([C:35]([F:37])([F:38])[F:36])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (38.7 mg, 0.153 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (51.4 mg, 0.128 mmol) and HATU (178.7 mg, 0.4700 mmol) was added DMF (2.0 mL) followed by DIPEA (159.5 mg, 1.234 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. To the resulting residue was added DCM (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (13.5 mg, 20%). LCMS calc. for C25H22F6N5O2 (M+H)+: m/z=538.2. found 538.2.