Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C=C(C(C)C)C=1S([O:19][CH:20]([C:27]1(O)[CH2:30][N:29]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[C:34]=2[NH:41][C:42]2[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=2[F:49])=[O:32])[CH2:28]1)[CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1)(=O)=O)C.[H-].[Na+].C(OCC)(=O)C>O1CCCC1>[O:26]1[CH2:25][CH2:24][O:23][CH:22]1[CH2:21][CH:20]1[C:27]2([CH2:30][N:29]([C:31]([C:33]3[C:34]([NH:41][C:42]4[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=4[F:49])=[C:35]([F:40])[C:36]([F:39])=[CH:37][CH:38]=3)=[O:32])[CH2:28]2)[O:19]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC(CC2OCCO2)C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(C1)OC2CC1OCCO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
1-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-(1,3-dioxolan-2-yl)ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (50 mg, 0.060 mmol) was dissolved in tetrahydrofuran (1 mL) and was cooled to 0° C. Sodium hydride (60 wt % dispersion in oil; 7 mg, 0.18 mmol) was added and the mixture was stirred at 0° C. for 45 minutes. The mixture was quenched with saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 6-{[2-(1,3-dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol, 94% yield): MS (EI) for C21H18F3IN2O4: 547 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[C:7]([CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]=1[OH:5].[C:44]([Si:48](Cl)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])([CH3:46])[CH3:45].N1C=CN=C1>ClCCl>[Si:48]([O:12][C:8]1[C:7]([CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:4]([OH:5])=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])([C:44]([CH3:47])([CH3:46])[CH3:45])([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1OC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1c(O)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Temperature: 40 °C
Reaction time: 21 h

Procedure:
2,3-Dimethoxy-5-methyl-6-(10-trityloxydecyl)-hydroquinone (80.4 g) was dissolved in dichloromethane (250 ml). tert-Butylchlorodiphenylsilane (26 ml) and imidazole (6.8 g) were added, and the mixture was stirred at 40° C. for 21 hours. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (9:1) to obtain the desired compound (40 g).
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10]S(=O)O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O)(=O)=O.[C:33](#[N:35])[CH3:34]>>[CH3:34][C:33]1[O:10][C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:35]=1
Reactant: O=S1O[C@H](c2ccccc2)C(c2ccccc2)(c2ccccc2)O1
Reactant: CC#N
Agent: O=S(=O)(O)C(F)(F)F
Product: CC1=NC(c2ccccc2)(c2ccccc2)[C@@H](c2ccccc2)O1
Temperature: 0 °C
Yield: 64 %

Procedure:
19 g (56.5 mmol) of (5R)-4,4,5-triphenyl-1,3,2-dioxathiolane 2-oxide in 90 ml of acetonitrile were introduced into a 250 ml three-necked flask fitted with magnetic stirrer, nitrogen/vacuum connection and 25 ml dropping funnel (with pressure equalization). After the mixture had been cooled to 0° C., 10 ml (113 mmol) of trifluoromethanesulfonic acid were added. The mixture was subsequently stirred at room temperature for a further sixteen hours. The solid by-product formed was filtered off with suction and rinsed with n-hexane, and the mother liquor was adjusted to a pH of 8 using sodium hydroxide solution (2.5 N) and finally freed from organic solvent in a rotary evaporator. After taking-up in dichloromethane, the product solution was dried over magnesium sulfate. After removal of the dichloromethane, the product was isolated in a yield of 64%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[Si:21]([O:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[Si:21]([O:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH:43][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1)([C:34]([CH3:35])([CH3:36])[CH3:37])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CC(C)(C)[Si](OCc1cccc(N)c1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=S)c1cnc(C)nc1Nc1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 50 °C
Yield: 103.4 %

Procedure:
A solution of 2.32 g (10 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 30 ml of 1,4-dioxan was treated with 1.4 ml (10 mmol) of triethylamine and 4.7 g (13 mmol) of 3-(tert-butyldiphenylsilyloxymethyl)aniline. The mixture was heated to 50° C. for 18 hours and then evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 5.6 g (100%) of ethyl 4-[3-(tert-butyldiphenylsilyloxymethyl)anilino]-2-methylthiopyrimidine-5-carboxylate as a colorless oil. [Mass spectrum (ESI) MH+ =558].
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CNCCO
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 25.2) and 2-methylamino-ethanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.97 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=450.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[CH2:21](O)[CH3:22]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)c(O)c1
Yield: 93 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-benzoic acid (2 g, 12.81 mmol) in absolute ethanol (30 ml) was added thionyl chloride (1 ml) drop wise at 0° C. After refluxing for overnight, the solvents were driven off, the residue was dissolved in dichloromethane (50 ml), cooled on ice bath, neutralized slowly with 1M NaHCO3, and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml) for one more time. Combined organic extracts were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography using dichloromethane to yield 2.2 g (93%) of product. MS (ESI+) m/z 185 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:26]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)#[CH:27]>>[CH:28]1([C:26]#[C:27][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=3[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C#CC1CCCC1
Reactant: NS(=O)(=O)c1cc(CO)ccc1NS(=O)(=O)CCc1ccc(Br)cc1
Product: NS(=O)(=O)c1cc(CO)ccc1NS(=O)(=O)CCc1ccc(C#CC2CCCC2)cc1
Yield: 11 %

Procedure:
The title compound was synthesized as described for Example 210 in 11% yield, starting from 2-[2-(4-bromo-phenyl)-ethanesulfonylamino]-5-hydroxymethyl-benzenesulfonamide and ethynyl-cyclopentane. Purification by preparative HPLC.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][N:16]1[CH2:17][CH2:18][CH:14]([C:6]2[NH:7][C:8](=[O:13])[C:9]3[C:4]([CH:5]=2)=[C:3]([CH3:2])[CH:12]=[CH:11][CH:10]=3)[CH2:15]1
Reactant: OCCBr
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCO)C3)cc12

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one hydrochloride (200 mg) and 2-bromoethanol (270 μl), 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (39 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28]C(=O)C)[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][C:14]2=[O:15])[CH2:9][CH2:8]1)=[O:6].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][C:14]2=[O:15])[CH2:11][CH2:12]1)=[O:6]
Reactant: COc1cc(OC(C)=O)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(O)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
1-[1-(2-Methoxy-4-acetyloxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.4 g) and sodium hydroxide (0.5 g) are dissolved in methanol (20 ml) and the mixture is stirred at room temperature for 1 hour. The solvent is concentrated and water is added to the residue, then the mixture is extracted with chloroform, dried with magnesium sulfate. The solvent is ditilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give 1-[1-(2-methoxy-4-hydroxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.3 g).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])O.[Na+].O.[CH2:19]1[O:21][CH:20]1[CH2:22][OH:23]>CO>[CH2:19]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])[CH:20]([CH2:22][OH:23])[OH:21]
Reactant: OCC1CO1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1OCC(O)CO
Temperature: 60 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
Under an argon atmosphere, L-ascorbic acid (10.0 g) and sodium hydrogen carbonate (9.54 g) were added to water and the resultant mixture was stirred at room temperature for 30 minutes, then, glycidol (8.41 g) was added thereto. Thereafter, the mixture was heated up to 60° C. and stirred for 5 hours. Thereto, methanol was added and filtration was performed. The filtrate was concentrated under reduced pressure, and 19.0 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:6/4/1), and concentration was performed under reduced pressure to obtain 2-O-glyceryl ascorbic acid (1.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=O)[CH2:11][CH:10]([C:14]([O:16]C)=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(=O)N(c2cccc(Cl)c2)C1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C(O)C1CCN(c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methyl 1-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylate (Ref: Tetrahedron, 62:4011-4017 (2006)). To a cold solution of MeOH (8.35 mL) (0° C.) was added thionyl chloride (0.335 mL, 4.59 mmol) dropwise. After 30 min, Intermediate 10 (1 g, 4.17 mmol) was added, and the reaction mixture was warmed to rt. The reaction mixture was then concentrated and the residue dissolved in EtOAc, washed with saturated NaHCO3, H2O and brine. The organic layers were dried over Na2SO4, filtered and concentrated to yield the desired product (1.04 g, 98%) as yellow oil. MS(ESI) m/z: 254.0 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:25])[O:19][CH2:20][C:21]#CCO)[CH:14]=[CH:15][CH:16]=1>C(Cl)CCl>[CH:15]1[CH:16]=[C:11]([Cl:10])[CH:12]=[C:13]([NH:17][C:18]([O:19][C:20]#[C:21][Cl:3])=[O:25])[CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1cccc(Cl)c1)OCC#CCO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccc(Cl)c1)OC#CCl

Procedure:
In another preparation on the same scale, the thionyl chloride and dimethylformamide in 25 ml of EDC were stirred at 65° while a warm solution of 4-hydroxy-2-butynyl N-(3-chlorophenyl)carbamate in 75 ml of EDC was added dropwise over 60 minutes. Barban (6.5 g) was obtained by evaporation of the solvent after 17 hours at 65° and analyzed by HPLC: barban 97.6% (w/w); biscarbanate -- 2.2% (w/w); bisurea -- 1.6% (w/w).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(NC(=O)OC(C)(C)C)ccc43)CC2C)cc1OC
Yield: 12.9 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (712 mg, 2.18 mmol) prepared in Reference Example 1 and tert-butyl N-(1,2,3,4-tetrahydro-6-quinolinyl)carbamate (1.35 g, 5.44 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (157 mg, yield: 13%) as a white crystal. (cis:trans=4.8:1)
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:2][C:3]1[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)N1CCC(c2ccccc2)=C(CO)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccccc2)=C(CCl)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (88 mg, 0.38 mmol) in DCM (2 mL) was added SOCl2 (0.67 mL, 9.50 mmol) at 0° C. After stirring at 0° C. for 15 min, the solution was concentrated to remove SOCl2, dried under high vacuum to give 1-(5-(chloromethyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one as crude product.
Reaction SMILES: [Na].N.Cl[CH:4]([CH2:14]Cl)[CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]>CCCCC>[CH2:6]([Si:7]([O:12][CH3:13])([O:8][CH3:9])[O:10][CH3:11])[CH2:5][CH:4]=[CH2:14]
Reactant: CO[Si](CCC(Cl)CCl)(OC)OC
Agent: N
Agent: [Na]
Solvent: CCCCC
Product: C=CCC[Si](OC)(OC)OC

Procedure:
23 g sodium (1 mole) are placed in a 500 ml flask and approximately 150 ml ammonia condensed in at -70 ° C. 123.6 g 3,4-dichlorobutyl trimethoxysilane (0.5 mole) is added dropwise to the deep-blue solution produced in the course of 1 hour at -55° C. while the reaction mixture visibly changes color. The ammonia is allowed to evaporate overnight from the colorless, highly viscous suspension produced, the colorless residue combined with 150 ml n-pentane, the NaCl (56.9 g ≅97.5 % of theory) removed by filtration and 88.2 of a colorless liquid corresponding to the expected amount is obtained after the solvent is drawn off. 75.7 g =85.9 % of theory of pure 3-butenyl trimethoxysilane are obtained therefrom by distillation (cf. table 1).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[O:13])[C:4]([CH3:23])([CH3:22])[CH2:3]1.I[Si](C)(C)C.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:23][C:4]1([CH3:22])[CH2:3][CH:2]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:13]
Reactant: Nc1ccccc1
Reactant: COc1cccc(C(=O)N2c3ccccc3C(O)CC2(C)C)c1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COc1cccc(C(=O)N2c3ccccc3C(Nc3ccccc3)CC2(C)C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
To a chilled solution of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone (500 mg, 1.6 mmol) in 10 ml dichloromethane was added slowly 0.8 ml iodotrimethylsilane (5.6 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 6 hours. Then the mixture was concentrated under vacuum. The residue was dissolved in 12 ml TIF. BaCO3 (630 mg, 3.2 mmol) and aniline (0.17 ml, 1.92 mmol) was added. The mixture was stirred at RT overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (1:4) to give (2,2-dimethyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone (150 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:7]([O:8][CH3:9])[C:4]=1[O:5][CH3:6].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:9][O:8][C:7]1[C:4]([O:5][CH3:6])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC

Procedure:
2,3,4-Trimethoxybenzenesulfonyl chloride is synthesized by reaction of pyrogallol trimethyl ether with chlorosulfonic acid in chloroform at 0° C. according to the procedure described in G. Pifferi and R. Monguzzi, Journal of Pharmaceutical Sciences, 1973, 62, 1393.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][NH:8][CH:4]([CH2:5]2)[CH2:3]1.Cl.Cl.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:3][C@@H:4]2[CH2:5][C@H:6]1[CH2:7][N:8]2[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1CC2CC1CN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1C[C@@H]2C[C@H]1CN2C
Temperature: 25 °C
Yield: 81.7 %

Procedure:
(1S,4S)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane.2HBr (6 g, 21.89 mmol) (which can be prepared by similar methods as described in Braish, T. F et al., J. Org. Chem. (1990), Vol. 55, pp. 1684-1687), 2-fluoro-5-nitrotoluene (2.61 g, 16.82 mmol) and K2CO3 (10.57 g, 76.46 mmol) in 30 mL NMP were heated at 110° C. for 14 h while stirring. The reaction mixture was cooled to ambient temperature, poured onto ice-water and stirred until precipitate formation. The yellow solid formed was collected by filtration and washed with 15% EtOAc/hexanes to provide 2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-nitrotoluene (3.4 g, 79%) in 98% purity; 1H NMR (DMSO-d6): δ 7.88-7.55 (m, 2H), 6.69 (d, 1H, J=8.8 Hz), 4.37 (s, 1H), 3.64 (dd, 1H, J=2.0 and 9.9 Hz), 3.38-3.55 (m, 2H), 2.81 (d, 1H, J=9.9 Hz), 2.65 (d, 1H, J=9.9 Hz), 2.33 (s, 3H), 2.23 (s, 3H), 1.87 (d, 1H, J=9.3 Hz), 1.75 (d, 1H, J=9.3 Hz); LCMS: purity: 98%; MS (m/e): 248 (MH+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15](=[O:17])[CH3:16])([OH:3])=[O:2].[CH3:18]O>>[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15](=[O:17])[CH3:16])([O:3][CH3:18])=[O:2]
Reactant: CO
Reactant: CC(=O)CCc1ccccc1CCCC(=O)O
Product: COC(=O)CCCc1ccccc1CCC(C)=O
Yield: 89.4 %

Procedure:
A solution of 117 g (0.5 mol) of 4-[2-(3-carboxypropyl)phenyl]-2-butanone, 9, in 200 ml of absolute methanol containing 2 equivalents (1.0 mol) of boron trifluoride methanol complex was refluxed for 16 hours. It was concentrated and the residue washed with H2O, then aqueous sodium bicarbonate solution. After drying, it was distilled to give 111 g of the keto ester 10, bp 132°-136° C/0.2 mm.
Reaction SMILES: O.NN.[CH2:4]([N:11]1[CH2:16][C@@H:15]2[CH2:17][C@H:12]1[CH2:13][N:14]2[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=1[F:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C>C(O)C.[Ni]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:13][C@@H:12]3[CH2:17][C@H:15]2[CH2:16][N:11]3[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[C:19]([F:27])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(N2C[C@@H]3C[C@H]2CN3Cc2ccccc2)c(F)c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2C[C@@H]3C[C@H]2CN3Cc2ccccc2)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Hydrazine hydrate (0.57 ml) was added to a suspension of 4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluoro-1-nitrobenzene (1.63 g, 5 mmol) in ethanol (35 ml) with stirring, followed by Raney nickel (˜1 g). The mixture was heated at 60° C. for 1.5 hours. More hydrazine hydrate (0.2 ml) and Raney nickel (˜0.5 g) were added and heating continued for a further 3 hours. The mixture was cooled and stirred with charcoal (0.5 g) for 1 hour and filtered. The filtrate was evaporated to give 1-amino-4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2.2.1}heptan-5-yl]-3-fluorobenzene (1.28 g, 86%) as an oil. MS: 287 (MH+); NMR(CDCl3); 1.8-1.95 (2H, dd); 2.73-2.9 (2H, dd); 3.17-3.5 (5H, m); 3.71 (2H, s); 4.12 (1H, s); 6.32-6.52 (3H, m); 7.18-7.35 (5H+CHCl3).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[C:8](=[O:24])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:23])[NH:21][OH:22])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:31](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:22]1[CH:31]=[N:23][C:20]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])=[O:24])=[N:21]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(C(=N)NO)c1)C1CCCCC1)OC
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2ncon2)c1)C1CCCCC1)OC
Temperature: 100 °C

Procedure:
To N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(N-hydroxycarbamimidoyl)phenethoxy)propanamide [Example 11, Step i)] (530 mg) in a 10 mL microwave vial was added trimethyl orthoformate (1 mL), sealed and heated at 100° C. for 20 min. The vial was then heated to 120° C. for 3 h before the addition of p-toluenesulfonic acid (3 mg) and then heated to 120° C. for a further 60 min. Ethanol was added (30 mL) and the solvent was evaporated to afford the sub-titled compound (500 mg). MS [M+H-MeOH]+=400 (MultiMode+)