Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]([C:19]2[N:20]=[N:21][N:22]([CH2:30][C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=3)[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:8][N:7]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:44][C:41]([F:42])([F:43])[C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=1)[CH2:30][N:22]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:19]([C:9]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]([CH2:5][CH2:4][OH:3])=[N:7][N:8]=2)[N:20]=[N:21]1
Reactant: CCOC(=O)Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Yield: 31.8 %

Procedure:
Dissolve [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-benzyl)-4H-[1,2,4]triazol-3-yl]-acetic acid ethyl ester (400 mg) in THF (10 mL). Add LAH (47 mg, soln in 10 mL of THF) at 0° C. and warm to RT overnight. Quench by slowly adding water (0.5 ml), 5N NaOH (0.5 ml) and then more water (3 ml). Filter reaction through Celite® to remove aluminum salts and then purify via radial chromatography using a gradient of 1:1 hexanes:EtOAc to 100% EtOAc to give the title compound (119 mg, 32%). MS (IS) 592.0 (M+1). Rf=0.11 (1:5 hexanes:EtOAc).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:38][CH:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:33][CH2:34]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCN1CCC(O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN3CCC(O)CC3)ccc21
Yield: 38.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)ethyl]-amide (50.0 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 1-(2-amino-ethyl)-piperidin-4-ol (72.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421. 1H NMR (DMSO-d6, 400 MHz): δ 8.00 (1H, m), 7.80-7.77 (1H, m), 7.65 (1H, m), 7.41-7.39 (1H, m), 7.26-7.24 (1H, m), 3.90 (1H, m), 3.75-3.72 (2H, t), 3.69 (3H, s), 3.37 (1H, m), 3.18 (2H, m), 2.07-2.02 (2H, m), 1.83-1.78 (2H, m), 1.32-1.29 (2H, m), 0.90-0.87 (2H, m), 2 —NH and —OH proton signals were not observed.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH:16]=O)=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].[CH3:30][C:31]([C:34]([O:36]C(C)(C)C)=[O:35])([CH3:33])[NH2:32]>>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH2:16][NH:32][C:31]([CH3:30])([C:34]([OH:36])=[O:35])[CH3:33])=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(CC=O)cc1F
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Product: CC(C)(NCCc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)O

Procedure:
Example 12 was synthesised using Intermediate 4 and Intermediate 8 following the same synthetic route as Example 11 (Scheme 12).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1ncnc(Cl)n1
Product: COc1cc(Nc2ncnc(Cl)n2)ccc1-n1cnc(C)c1
Yield: 50 %

Procedure:
This compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,4-dichloro-1,3,5-triazine in analogy to example 2a. The compound precipitated from methanol in 50% yield.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=1.[CH:19]1([C:22]#[N:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1>O>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)[CH:13]=1
Reactant: N#CC1CC1
Reactant: Fc1cc(Br)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2cc(Br)ccn2)CC1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
LiHMDS (1M in toluene, 17.6 mL, 17.6 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) mixture of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol), cyclopropanecarbonitrile (1.25 mL, 17 mmol, 3 eq), 4 Å molecular sieves and toluene (20 mL). The reaction mixture is allowed to warm to II, stirred for 16 h, poured into H2O and filtered. The filtrate is diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 9:1), to afford 620 mg of the title compound as a white solid: ESI-MS: 223.1/225.1 [M+H]+; tR=4.22 min (System 1); TLC: Rf=0.25 (Hex/EtOAc, 9:1).
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]#[C:17][C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>C(O)C>[C:1]1([C:7]2[C:15]([C:16]#[C:17][C:18]([O:20][CH3:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)C#Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C#Cc1c(-c2ccccc2)nn2ccccc12
Yield: 48.2 %

Procedure:
3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)propiolic acid (10.33 g) was added to a mixture of sodium hydroxide (3.15 g) and 95% ethanol (103 g), and then dimethyl sulfate (4.97 g) was added to the mixture. The reaction mixture was heated at 60° to 80° C. for 3 hours and 20 minutes. Ethanol was evaporated in vacuo. Water was added to the residue and extracted with chloroform (50 ml×3). Combined extract was washed with a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give crystals of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propiolate (5.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[N:11][S:10][N:9]=2)=[C:4]([CH:13](Br)Br)[CH:3]=1.S([O-])([O-])(=O)=[O:17].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[N:11][S:10][N:9]=2)=[C:4]([CH:3]=1)[CH:13]=[O:17]
Reactant: Clc1ccc(-c2cnsn2)c(C(Br)Br)c1
Reactant: O=S(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Cl)ccc1-c1cnsn1
Temperature: 0 °C

Procedure:
A stirred solution of 3-[4-chloro-2-(dibromomethyl)phenyl]-1,2,5-thiadiazole (0.452 g, 1.23 mmol) and potassium sulfate (0.334, 2.45 mmol) in concentrated H2SO4 (20.0 mL) was heated to 90° C. for 1.5 h. The solution was poured into ice water, basified with saturated aqueous sodium carbonate and extracted into EtOAc. The organic phase was dried (Na2SO4) and reduced in vacuo. 5-Chloro-2-(1,2,5-thiadiazol-3-yl)benzaldehyde was isolated as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.70 (s, 2H), 8.05 (s, 1H), 8.82 (s, 1H), 10.28 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21])[CH:2]=1.[OH-].[Na+:33]>O>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[Na+:33].[Na+:33]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)O)C(=O)O)cc3)c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1

Procedure:
All routes start with saponification of Pemetrexed IM8 in water at IT=20° C. to 30° C. using 3.25 eq of NaOH. Upon complete conversion an aqueous solution of Pemetrexed Disodium with a pH of 13.0 to 13.5 is obtained. Starting from this mixture the desired route can be accessed by addition of HCl to adjust the pH to a certain value (depending on the route, FIG. 20).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)#[N:19]>>[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1)#[N:19]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2C#N)cc1
Yield: 60 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 2-cyanophenylboronic acid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 7.4-7.55. (m, 3H), 7.6 (d, 2H), 7.65 (td, 2H), 7.8 (d, 1H). MS (M+H, 321).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH2:21][CH2:22][CH2:23][CH3:24])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH2:21][CH2:22][CH2:23][CH3:24])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1
Reactant: CCCCC(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)C(=O)OCC
Agent: [Pd]
Product: CCCCC(C)(Cc1ccc(OCCN)cc1)C(=O)OCC
Yield: 96.1 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-butyl-2-methylpropionate (2.73 g), which is the product of Reference example 10(f), and palladium on carbon (5%, 270 mg) and the reaction mixture was treated to afford the title compound (2.42 g) as a syrup.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([NH:11][C:12]1[N:13]=[C:14]2[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]2=[N:16][CH:17]=1)=[O:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([NH:11][C:12]1[N:13]=[C:14]2[CH:20]=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1)=[O:10]
Reactant: C[C@H]1CCCC[C@H]1NC(=O)Nc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: C[C@H]1CCCC[C@H]1NC(=O)Nc1cnc2[nH]ccc2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 31.4 %

Procedure:
A mixture of 1-(cis-2-methyl-cyclohexyl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.3 g, 0.7 mmol), tetrabutyl ammonium fluoride (1 M in THF, 4.6 mL, 4.6 mmol) and ethylene diamine (0.46 mL, 4.2 mmol) in 5 mL of N,N-dimethylformamide was stirred at 80° C. for 20 h, then concentrated. The resulting residue was triturated in methanol, and solid was isolated by filtration, washing with ether, and dried to afford 0.060 g (30%) of 1-(cis-2-methyl-cyclohexyl)-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH3:28][NH2:29]>>[CH3:28][NH:29][C:22](=[O:23])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[CH:15][CH:16]=1
Reactant: CN
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)NC
Yield: 74 %

Procedure:
The title compound (0.23 g, 74%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.8 mmol) obtained in example 26 and methylamine (40% solution) (2 mL) by an analogous procedure to that described in example 32. mp: 97-99° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=O.Cl.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(Cl)Cl>[CH3:24][N:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:5](=[O:4])[C:7]3([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[N:13]=2)=[CH:17][CH:18]=1)[CH3:25]
Reactant: COC(=O)C1(NC(=O)c2ccc(CN(C)C)cc2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
29 ml of 2N aqueous sodium hydroxide solution was added to a solution of 1.85 g (5.8 mmol) of 1-[[[4-[(dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester in 29 ml of tetrahydrofuran, and the mixture was heated under reflux overnight. After the reaction solution was neutralized by concentrated hydrochloric acid, the reaction mixture was distilled off under reduced pressure. 30 ml of methylene chloride, 1.76 g (17 mmol) of triethylamine and 1.67 g (8.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the residue, and the mixture was stirred for 1 hour. The reaction mixture was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.33 g (80%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1COCC1.O.[OH-].[Na+]>[CH2:20]([O:19][C:17]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reaction time: 12 h
Yield: 93 %

Procedure:
A solution of 4-aminomethyl-1-Boc-piperidine (5.00 g, 23.4 mmol) in THF (60 mL), water (14 mL) and 5 N NaOH (46 mL) was treated with benzyl chloroformate. After 12 h, the mixture was partitioned between EtOAc and water and the aqueous phase washed with EtOAc (3×). The combined extracts were washed with water, brine and concentrated to afford 7.6 g (93%) of the title compound which was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[CH2:9]([O:16][C@@H:17]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][C:19](OC)=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:16][C@@H:17]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][C:19](=[O:20])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCC[C@@H](CC(=O)OC)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[C@@H](CC(=O)CC(=O)OC(C)(C)C)OCc1ccccc1
Temperature: -50 °C
Reaction time: 0.75 h
Yield: 59.4 %

Procedure:
A solution of 48.7 g of t-butyl acetate in 50 ml of dried THF was then added dropwise to the solution from a dropping funnel at the same temperature over 30 minutes, followed by stirring for 45 minutes. The resulting reaction mixture was further cooled to -50° C., and a solution of 45.4 g of methyl (S)-3-benzyloxyheptanoate in 50 ml of dried THF was added thereto over 30 minutes, followed by stirring for 2 hours while maintaining at that temperature. The reaction mixture was poured into a saturated ammonium chloride aqueous solution and extracted with diethyl ether. The extract was washed with a sodium chloride aqueous solution, and the solvent was removed by distillation under reduced pressure to obtain 67 g of a crude product, which was then purified by silica gel column chromatography to obtain 36 g (53.3%) of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=C.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=[O:18]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ccc(C#N)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
A solution of 2-oxo-1-(2-propen-1-yl)-1,2-dihydro-7-quinolinecarbonitrile (600 mg, 2.9 mmol) in 1,4-dioxane (30 ml) and water (20 ml) was cooled to 0° C. and treated with OsO4 (4% in water, 3 ml) and sodium periodate (1.4 g, 6.67 mmol). The reaction was warmed to rt; 0.6 g and then 3.7 g more of sodium periodate were added. After 4 h in total, the solvent was evaporated and residue partitioned between water and 20% methanol-DCM. The phases were separated and the organic phase was dried and evaporated to afford the desired compound (660 mg, 107%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:10])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[NH3:11]>>[CH3:10][C:4]1[C:3]([CH2:2][NH2:11])=[CH:8][CH:7]=[C:6]([CH3:9])[N:5]=1
Reactant: N
Reactant: Cc1ccc(CCl)c(C)n1
Product: Cc1ccc(CN)c(C)n1

Procedure:
The solution of 3-(chloromethyl)-2,6-dimethylpyridine (850 mg, 5.5 mmol) in ammonia solution (10 mL) was stirred at 90° C. for 2 hours and then concentrated to give the crude product which was used for next step directly without further purification. LCMS (ESI) m/z=137.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH:31]O.[OH-].[Na+]>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:4]2([CH2:1][CH2:2][CH2:3][OH:31])[O:9][C:8](=[O:10])[N:7]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[CH2:6][CH2:5]2)=[CH:29][CH:28]=1
Reactant: OO
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](N2CCC(CCCO)(c3ccc(F)cc3)OC2=O)C1

Procedure:
The two diastereomers of (3S)-tert-butyl 3-(6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate were prepared from (3S)-tert-butyl 3-(6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate by treatment with (i) BH3 in THF and (ii) H2O2 and NaOH.
Reaction SMILES: [CH2:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=1)[CH:2]=[CH2:3].NN>CCO>[CH2:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(N2C(=O)c3ccccc3C2=O)n[nH]1
Agent: NN
Solvent: CCO
Product: C=CCOc1cc(N)n[nH]1
Temperature: 50 °C

Procedure:
To a mixture of triphenylphosphine (2.75 g, 10.5 mmol), allyl alcohol (0.714 ml, 10.5 mmol), and 2-(5-hydroxy-1H-pyrazol-3-yl)isoindoline-1,3-dione (2.000 g, 8.73 mmol) in DMF (25 mL) at RT was slowly added DIAD (2.04 ml, 10.5 mmol). After 18 hrs the solution was concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic fraction was dried with sodium sulfate, concentrated in vacuo, and purified by silica gel chromatography using 40-70% Hexanes:EtOAc to afford 2-(5-(allyloxy)-1H-pyrazol-3-yl)isoindoline-1,3-dione as a light yellow solid. MH+=270.1. Step 2B: To a mixture of 2-(5-(allyloxy)-1H-pyrazol-3-yl)isoindoline-1,3-dione (0.684 g, 2.54 mmol) in EtOH (10 mL) at RT was added anhydrous hydrazine (0.319 ml, 10.2 mmol). The solution was heated at 50° C. for 18 hrs before cooling to 0° C. The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo to afford crude 5-(allyloxy)-1H-pyrazol-3-amine that was advanced without further purification. MS: Found M+H+=147.2.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[N:34]=[CH:33][CH:32]=[N:31]3)=[CH:26][CH:25]=2)=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])[CH:9]=1.O.CO>CC1CCCO1>[F:3][C:4]1[C:5]([C:24]2[CH:25]=[CH:26][C:27]([N:30]3[N:34]=[CH:33][CH:32]=[N:31]3)=[CH:28][CH:29]=2)=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Potassium hydroxide (1.30 g, 23.2 mmol) was added to a solution of ethyl (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate (1.54 g, 3.33 mmol) in 2-methyltetrahydrofuran:water (2::1 42.5 mL) and the solution was stirred at rt overnight. Methanol (5 mL) was added and the reaction was heated to 60° C. The reaction mixture was stirred at this temperature for 2 h. The reaction was concentrated and triturated in 3 M aq HCl. The solid was collected via filtration and washed with water (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.39 g, 96.1%). MS (LCMS) m/z 435.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3 H) 2.13-2.30 (m, 0 H) 2.41-2.61 (m, 1 H) 3.17 (s, 3 H) 3.89-4.13 (m, 2 H) 6.59 (d, J=7.81 Hz, 1 H) 6.56-6.63 (m, 1 H) 7.79 (dd, J=8.78, 1.76 Hz, 3 H) 8.09 (d, J=6.83 Hz, 1 H) 8.12-8.17 (m, 2 H) 8.19 (s, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:19]1[CH:20]=[C:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[CH:24]=1.[OH-].[NH4+].CCCCCCCCCCCC>[Cu]I.C(N(CC)C(=O)C1C(=CC=CC=1)O)C.O.C(OCC)(=O)C>[CH3:26][C:21]1[CH:20]=[C:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:24]=[C:23]([CH3:25])[CH:22]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: CCN(CC)C(=O)c1ccccc1O
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-n2ccc3ccccc32)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 88.6 %

Procedure:
CuI (10 mg, 0.05 mmol), N,N-diethylsalicylamide (10 mg, 0.05 mmol), indole (176 mg, 1.5 mmol) and K3PO4 (425 mg, 2.0 mmol) were put into a screw-capped test tube with a Teflon-lined septum. The tube was then evacuated and backfilled with argon (3 cycles). 5-Bromo-m-xylene (136 μL, 1.0 mmol) was added by a syringe. The reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was allowed to reach room temperature. Ethyl acetate (˜2 mL), water (˜10 mL), ammonium hydroxide (˜0.5 mL) and dodecane (227 μL) were added. The organic phase was analyzed by GC or GC-MS. The reaction mixture was further extracted by ethyl acetate (4×10 mL). The combined organic phases were washed with brine and dried over Na2SO4. Solvent was removed in vacuo and the yellow residue was purified by column chromatography on silica gel using hexane/ethyl acetate (10:1) as eluent to afford the desired product as a brown solid (196 mg, 89% yield).