Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(Br)n(COCc2ccccc2)c1C=O
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccn(COCc2ccccc2)c1C=O
Yield: 103 %

Procedure:
To 43 ml of toluene solution containing 3.66 g (10.0 mmol) of ethyl 1-benzyloxymethyl-5-bromo-2-formyl-1H-pyrrol-3-carboxylate obtained in Reference example 17-(c) were added 2.1 ml of N,N-diisopropylethylamine and 0.4 g of 5% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 6 hours. After completion of the reaction, insoluble material was removed by filtration from the reaction mixture, ethyl acetate was added to the filtrate, and the filtrate was washed successively with water and a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.96 g the title compound as a pale yellowish solid substantially quantitatively.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO.O>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:8]2([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:19]1
Reactant: O=C(C(=O)c1ccncc1)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccncc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 1 -phenyl-2-(4-pyridinyl)ethanedione (500 mg, 2.42 mmol) and 2-guanidinobenzimidazole (1.0 g, 6.0 mmol) in methanol (10 mL) was treated with a solution of sodium hydroxide (40 mg, 1.0 mmol) in 1 mL of water. The title compound was isolated as pale yellow crystals (45 mg, 3% yield). 1H NMR (300 MHz, d6 -DMSO) δ 11.5 (br s, NH, 1 H), 1 1.0 (br.s, NH, 1H), 10.0 (br s, NH, 1 H), 8.6 (br s, NH, 1 H), 8.4 (m, 2 H), 7.4-6.8 (m, 15H); MS (ESI) m/z 526 [M+H]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)=[O:23]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: ClCCl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCCC3)c1ccco1
Yield: 79.6 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), 2-furoyl chloride (0.075 mL, 0.76 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (12 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2-furamide (0.17 g). MS (ESI) m/z 310 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]=[CH:3][C:2]=1[C:12]([O:14]CC)=O.O.[NH2:18][NH2:19]>C(O)C>[NH:18]([C:12]([C:2]1[N:1]=[CH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1)=[O:14])[NH2:19]
Reactant: NN
Reactant: CCOC(=O)c1cnc(C(=O)OCC)cn1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(C(=O)NN)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A mixture of diethyl pyrazine-2,5-dicarboxylate (1.75 g, 7.81 mmol) and ethanol (15 mL) was heated to 75° C. to obtain a homogeneous solution. After cooling to room temperature, a solution of hydrazine monohydrate (0.281 g, 7.03 mmol) in ethanol (3.5 mL) was added to the solution dropwise over 4 hours. After stirring at room temperature overnight, a solid had precipitated out of the reaction mixture. The solid was collected by filtration and dried under vacuum to give the title compound (1.05 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C1C=CN=CC=1)C>[C:16]([NH:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: COc1ccc(OC)c2c(N)ccnc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: COc1ccc(OC)c2c(NC(C)=O)ccnc12

Procedure:
A suspension of 3 g (14.7 mmol) of 4-amino-5,8-dimethoxyquinoline and of 0.72 g (5.88 mmol) of DMAP in 30 mL of acetic anhydride is stirred at ambient temperature for 24 hours. After concentrating on a rotary evaporator, the reaction medium is washed with 40 mL of saturated NaHCO3 solution and then extracted with CHCl3 (3 times 50 mL). The extracts are dried over MgSO4 and the solvent is evaporated off, followed by evaporation of the remaining acetic anhydride by azeotropic entrainment with benzene. 2.7 g of the expected derivative are obtained in the form of a yellow powder.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=[O:21])C>>[CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([OH:21])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: CC(=O)OC(C)=O
Product: CC(C)Cn1cnc2c(O)nc3ccccc3c21

Procedure:
To 70 ml of acetic anhydride was added 13.0 g (0.0539 mole) of 1-isobutyl-1H-imidazo[4,5-c]quinolin-5-oxide. The solution was heated on a steam bath for 10 minutes, then allowed to cool. The precipitate was separated by filtration, washed with ethanol, and dried. Recrystallization from N,N-dimethylformamide provided 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-ol, m.p. >300° C. Analysis: Calculated for C14H15N3O: %C, 69.7; %H, 6.3; %N, 17.4; Found: %C, 69.8; %H, 6.4; %N, 17.6.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[N:5]=[C:6]([C:14]2[CH:35]=[CH:34][C:17]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[C:16]([C:36]([F:39])([F:38])[F:37])[CH:15]=2)[C:7]2[CH:12]=[CH:11][N:10]([CH3:13])[C:8]=2[N:9]=1)#[N:3]>CCOC(C)=O>[ClH:1].[CH3:13][N:10]1[C:8]2[N:9]=[C:4]([C:2]#[N:3])[N:5]=[C:6]([C:14]3[CH:35]=[CH:34][C:17]([O:18][CH2:19][CH2:20][CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[C:16]([C:36]([F:37])([F:38])[F:39])[CH:15]=3)[C:7]=2[CH:12]=[CH:11]1
Reactant: Cn1ccc2c(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1ccc2c(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc21
Reaction time: 1 h

Procedure:
A 4 M solution of hydrogen chloride in EtOAc (2 mL) was added to a solution of tert-butyl 4-{2-[4-(2-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (232 mg) in EtOAc (2 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration, whereby 7-methyl-4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (198 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C@:20]54[O:28][C@H:19]5[CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].FC(F)(F)C(O)=O.[CH2:37]([OH:40])[CH2:38][CH3:39]>>[CH2:37]([O:40][C@H:19]1[C@:20]2([OH:28])[C@:21]([CH3:27])([CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25]2)[C@@H:16]2[C@H:17]([C@H:12]3[C@:13]([CH3:29])([CH2:14][CH2:15]2)[C@@H:9]([C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:10][CH2:11]3)[CH2:18]1)[CH2:38][CH3:39]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: CCCO
Solvent: O=C(O)C(F)(F)F
Product: CCCO[C@@H]1C[C@H]2[C@@H]3CC[C@H]([C@H](C)CCCC(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@H](O)C[C@]12O

Procedure:
In a flask (50 ml) fitted with a condenser cholesterol 5α,6α-epoxide (100 mg., 0.25 mmol) in 1-propanol (20 ml) solution containing trifluoroacetic acid (1.0 ml) is refluxed for 1 hour. With vacuum evaporation the solvent is removed. The oily residue is dissolved in benzene (10 ml), extracted with 5% aqueous sodium bicarbonate (2 ml×2) and with water, and dried with anhydrous sodium sulfate. After vacuum evaporation the amorphous solid residue is purified by silica gel G-60 column liquid chromatography employing chloroform-methanol gradient elution. Selected fractions provide the product, 6β-n-propoxy-3β,5α-dihydroxycholestane. (45 mg).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].[OH-].[Na+]>O1CCCC1.O>[CH2:29]([O:28][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH:25]([CH3:26])[CH3:27])=[O:23])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(C(=O)NC(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(C(=O)NC(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
2-Ethoxy-3-[4-(2-{4-(isopropylaminocarbonyl)phenyl}ethoxy)phenyl]propanoic acid ethyl ester (described in Example 106) (1 g; 2.34 mmole) was dissolved in tetrahydrofuran (10 ml). Lithium hydroxide (0.056 g; 2.34 mmole) dissolved in water (6 ml) was added slowly in portions during 20 minutes. The reaction mixture was stirred at room temperature for 3 hours and then diluted with water followed by careful evaporation of tetrahydrofuran. The residual water phase was extracted once with diethyl ether, then acidified and extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried with sodium sulfate and evaporated. The residue was dissolved in methanol (10 ml) and sodium hydroxide (0.109 g; 1.73 mmole) in water (3.5 ml) was added. The solution was evaporated and the residue redissolved in water. Freeze drying gave 0.643 g (65.2% yield) of 2-ethoxy-3-[4-(2-{4-(isopropylaminocarbonyl)phenyl}ethoxy)phenyl]propanoic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+]>C(#N)C>[CH2:11]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc2ccncc2c1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(CN2CCc3ncccc3C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
1,6Naphthyridine (13.7 g, 105 mmol) and benzyl bromide (36.05 g, 210 mmol) were combined in acetonitrile (200 ml) and heated to reflux until no 1,6-naphthyridine was visible by thin layer chromatography. After removal of the solvent in vacuo, the residue was washed several times with ether and dissolved in methanol (700 ml). Water (250 ml) was added, and the solution cooled to 0°; portionwise addition of sodium borohydride (20.8 g, 550 mmol) brought about vigorous gas evolution and a slight rise in temperature. The reaction mixture was allowed to warm to room temperature and stir for 18 hours. The solvent was then removed in vacuo and the residue partitioned between water (750 ml) and methylene chloride (300 ml). The aqueous layer was extracted with additional methylene chloride (2×300 ml) and the combined organic extracts were washed once with water and once with saturated aqueous sodium chloride. Removal of solvent provided a dark amber foam, which was purified by column chromatography (99:1 methylene chloride:methanol) to yield the title product (12.1 g, 54 mmol, 51% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:35])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cccc(C2CC3(NC(=O)NC3=O)c3cc(Br)ccc3O2)c1
Solvent: C1COCCO1
Product: COc1cccc(C2CC3(NC(=S)NC3=O)c3cc(Br)ccc3O2)c1
Yield: 38.5 %

Procedure:
A suspension of 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 0.64 mmol) and Lawesson's Reagent (250 mg, 0.62 mmol) in dry 1,4-dioxane (20 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-methoxyphenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 45%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].C1(C)C=CC(S(O[CH2:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH:32]1([CH2:31][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:35][CH2:34][CH2:33]1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CCC2)c(=O)[nH]c1=O
Yield: 52.6 %

Procedure:
5-Ehtyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclobutyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (179 mg, yield: 52.6%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1C
Product: CC(=O)N[C@H]1C[C@@H](C)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4S*)-4-amino-2-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f69) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[N:10]([O-])=O.[Na+]>Cl>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][NH2:10]
Reactant: O=N[O-]
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Product: NNc1c(Cl)cccc1Cl
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 227.7 %

Procedure:
To a cold solution of 2,6-dichloroaniline (10.0 g, 61.72 mmol) in conc. HCl was added aqueous solution of sodium nitrite (5.11 g, 74.00 mmol) at −15° C. The reaction mass was stirred at 0-10° C. for 15 minutes. The reaction mass was filtered off to remove insolubles and stannous chloride in conc. HCl (34.7 g, 150 mmol) was added to the filtrate. The reaction mass was further stirred at −15° C. for 30 min and filtered to afford 15.00 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.18-7.28 (m, 1H), 7.39-7.52 (m, 2H), 10.30 (br s, 3H); MS (m/z): 176.90 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:18]Cl>C(Cl)Cl>[Cl:18][C:6]1[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: ClCl
Reactant: COc1ccc(CCCCCCO)cc1OC
Solvent: ClCCl
Product: COc1cc(Cl)c(CCCCCCO)cc1OC
Reaction time: 16 h

Procedure:
To 1.40 g of 6-(3,4-dimethoxyphenyl)hexan-1-ol in 25 mL of methylene chloride cooled in a ethanol-dry ice bath was added 4.6 mL of 1.35M chlorine in methylene chloride. The reaction mixture was kept at -75° for 1.5 hours, at -18° for 16 hours and then at 0° for 24 hours. After concentration under reduced pressure, the crude product was purified by HPLC to give 6-(6-chloro-3,4-dimethoxyphenyl)hexane-1-ol as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave a molecular ion at m/z 272 (C14H21ClO3).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:8][C:3]([CH3:9])([CH2:2][NH:1][S:18]([CH3:17])(=[O:20])=[O:19])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CNS(C)(=O)=O
Reaction time: 48 h
Yield: 31.2 %

Procedure:
To a solution of methyl 3-amino-2,2-dimethylpropanoate (249 mg, 1.90 mmol) and Et3N (0.80 mL, 5.70 mmol) in 2 mL CH2Cl2 was added methanesulfonyl chloride (0.29 mL, 3.80 mmol). The reaction was stirred for 2 days, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCl3, and chromatographed (1:1 hex:EtOAc) to provide methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate (124 mg, 31%) as a clear oil. 1H NMR (400 MHz, CDCl3), 4.95 (t, 1H, J=6.8 Hz), 3.69 (s, 3H), 3.16 (d, 2H, J=6.8 Hz), 2.95 (s, 3H), 1.24 (s, 6H). Methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate was hydrolyzed using aqueous NaOH to provide 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoic acid, which was used without further purification. 1H NMR (400 MHz, CDCl3), δ 10.28 (br. s, 1H), 5.56 (br. s, 1H), 3.14 (s, 2H), 2.94 (s, 3H), 1.25 (5, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.83 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (320 mg, 0.83 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.72 ml, 4.16 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (427 mg, 0.91 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (246 mg, 0.40 mmol, 49% yield) as a clear oil: LCMS (ES) m/e 571, 573 (M, M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Cl[C:45]1[N:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:47][CH:46]=1>COCCOC>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[N:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CNS(C)(=O)=Nc1ccc(Cl)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Solvent: COCCOC
Product: CNS(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)nc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(6-chloropyridin-3-yl)-N-methyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 13 (Step 3) using 1,2-dimethoxyethane as a solvent. LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=687 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C=O)C>[S:14]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cccnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (16.7 g, 114 mmol) in DMF (150 mL) was added to a chilled (0° C.) mixture of dry DMF (300 mL) and sodium hydride (4.88 g, 122 mmol, 60% dispersion in mineral oil). This was stirred at 0° C. for 30 minutes, and a DMF solution (100 mL) of tosyl chloride (21.8 g, 114 mmol) was then added slowly over a ten minute period. The mixture was then allowed to warm to room temperature and stirred for 3 hours. Water (500 mL) was then added, and the solids were collected to give 1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (29.7 g, 87%). 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.43-8.49 (m, 2H), 8.08-8.13 (m, 2H), 7.44-7.50 (m, 3H), 2.37 (s, 3H).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].ClC(Cl)(Cl)C(O[CH:26]([CH3:28])[CH3:27])=N.COCCOC.FC(F)(F)S(O)(=O)=O>CCCCCCC>[C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([O:20][CH:26]([CH3:28])[CH3:27])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](O)Cc1cccc(OC(=O)C(C)(C)C)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1cccc(OC(=O)C(C)(C)C)c1)OC(C)C
Yield: 95.6 %

Procedure:
Methyl (2S)-3-(3-pivaloyloxyphenyl)-2-hydroxypropionate (11 kg), 2,2,2-trichloro-1-isopropoxyethanimine (20 kg, 98 mol), 1,2-dimethoxyethane (10 L), and heptane (44 L) were mixed and stirred, and the resultant solution was cooled to 7° C. Trifluoromethanesulfonic acid (2.36 kg, 15.7 mol) was added dropwise to the reaction mixture over a period of 36 minutes, followed by stirring the reaction mixture at 25° C. for 19 hours. The reaction mixture was cooled to 7° C., to which heptane (66 L) was then added. The reaction mixture was then stirred for 45 minutes, followed by filtering off a white crystal of trichloroacetoamide. Water (55 L) was added to the filtrate for separating. Then, the organic layer was washed with a 5% sodium bicarbonate aqueous solution (52 L) twice and with water (55 L), followed by vacuum concentration to obtain 12.1 kg of the title compound (yield: 96%).