Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S].[S:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[CH3:16][C:17]([CH3:19])=[CH2:18]>>[S:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:17]([C:15]1[CH:14]=[CH:13][S:12][C:11]=1[C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:19])([CH3:18])[CH3:16].[CH3:9][C:7]([CH3:10])=[CH2:8]
Reactant: CC(C)(C)c1cccs1
Agent: C=C(C)C
Agent: [S]
Solvent: c1ccsc1
Product: CC(C)(C)c1ccsc1C(C)(C)C

Procedure:
The alkylation process results in the substitution of an alkyl group for a hydrogen atom in the sulfur-containing starting material and causes a corresponding increase in molecular weight over that of the starting material. The higher molecular weight of such an alkylation product is reflected by a higher boiling point relative to that of the starting material. For example, the conversion of thiophene to 2-t-butylthiophene by alkylation with 2-methylpropene results in the conversion of thiophene, which has a boiling point of 84° C., to a product which has a boiling point of 164° C. and can be easily removed from lower boiling material in the feedstock by fractional distillation. Conversion of thiophene to di-t-butylthiophene by dialkylation with 2-methylpropene results in a product which has an even higher boiling point of about 224° C. Alkylation with alkyl groups that add a large rather than a small number of carbon atoms is preferred since the products will have higher molecular weights and, accordingly, will usually have higher boiling points than products which are obtained through alkylation with the smaller alkyl groups.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>CC(C)=O>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: BrCCCCBr
Reactant: NC(=O)c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(OCCCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxy-2-nitrobenzamide 3 (0.7 g, 0.0038 mol) in 20 mL acetone was added potassium carbonate (2.0 g, 0.015 mol). The reaction mixture was stirred at room temperature for 10 min. Then 1,4-dibromobutane 4 (1.8 mL, 0.015 mol) was added. The resulting mixture was refluxed for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC). Potassium carbonate was filtered and washed with acetone. The combined filtrate and washings were evaporated. The residue was triturated with methyl tert-butyl ether; the solid separated was filtered and dried to give 4-(4-bromobutoxy)-2-nitrobenzamide 5. White solid (0.85 g, 70%). 1H NMR (400 MHz, CDCl3): δ 1.98-2.03 (m, 2H); 2.04-2.09 (m, 2H); 3.49 (t, J=6.0 Hz, 2H); 4.08 (t, J=5.2 Hz, 2H); 5.80 (br s, 2H); 7.13 (dd, J=2.4, 8.4 Hz, 1H); 7.47-7.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CO>C(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C@@H:25]([OH:27])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc([C@H](C)O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
56.36 g of boran complex of (3aR,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2c][1,3,2]oxazaborole (1 equivalent) is dissolved under nitrogen in methylenchloride, and the solution is cooled to 0° C. A 1M solution of 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl]propoxy}-3-methoxy-phenyl)-ethanone (Iloperidone; 1 equivalent) in methylenchloride is added via a dropping funnel over 90 minutes while the internal temperature is maintained at 0° C.±2° C. After the addition is complete, the mixture is stirred at 0° C. for 20 hours. The reaction mixture is then poured into precooled methanol (0-5° C.) during 1 hour. The solution is warmed to room temperature and stirred until the H2 evolution ceases. The solution is concentrated by distillation and the residue dried in vacuum, treated with methanol and stirred for about 1 hour at 50° C. and an additional hour at 0° C. The product is isolated by filtration and dried under reduced pressure for 3 hours at 50° C. The title compound is obtained (white crystals).
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[CH:16]([C@:17]3([CH3:44])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:41]([CH2:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:20]2[C:21]([CH3:32])([CH3:31])[C@H:22]3[C@:17]([CH3:44])([CH2:18][CH:19]=2)[C@@H:16]2[C@:25]([CH3:30])([C@@:26]4([CH3:29])[C@H:13]([CH2:14][CH2:15]2)[C@H:12]2[C@H:45]([C:48]([CH3:50])=[CH2:49])[CH2:46][CH2:47][C@:11]2([C:9]([OH:10])=[O:8])[CH2:28][CH2:27]4)[CH2:24][CH2:23]3)=[CH:34][CH:35]=1)([OH:43])=[O:42]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 24 h

Procedure:
A mixture of 3-(4-((1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-3a-(benzyloxycarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)phenyl)propanoic acid (60 mg, 0.089 mmol) and 10% Pd/C (28.3 mg, 0.027 mmol) in Ethyl acetate (2 mL) was stirred under 1 ATM of H2 for 24 hours. LCMS indicated the completion of the reaction. The reaction mixture was filtered and the white solid was collected. The solid was purified by Prep. HPLC to provide the desired product, (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid, as white solid (10.32 mg, 30%). LCMS: m/e 585.59 (M−H)−, 4.38 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.91 (s, 3H), 0.93 (s, 3H), 1.00 (s, 6H), 1.02 (s, 3H), 1.05-1.72 (m, 17H), 1.71 (s, 3H), 1.84-1.95 (m, 2H), 2.10 (dd, J=17.58, 6.44 Hz, 1H), 2.20 (d, J=11.72 Hz, 1H), 2.30-2.39 (m, 1H), 2.60 (s, 2H), 2.85 (t, J=7.62 Hz, 2H), 3.02 (td, J=10.25, 5.27 Hz, 1H), 4.61 (br. s, 1H), 4.74 (s, 1H), 5.23 (d, J=5.27 Hz, 1H), 6.94 (d, J=7.62 Hz, 1H), 6.98 (s, 1H), 7.12 (d, J=8.20 Hz, 1H), 7.20 (t, J=7.62 Hz, 1H).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-chlorophenol (6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.3 mg, 26.9% yield) as a thick oil: 1H NMR δ 7.36 (s, 1H), 7.35-7.22 (m, 7H), 7.12 (m, 2H), 6.97 (apparent d, 1H, J=7.2 Hz), 6.77 (m, 2H), 5.23 (m, 1H), 3.18 (m, 2H), 2.70 (m, 2H), 2.50 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 491.4 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3]/[C:4](/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:5]\[CH2:6][NH:7][C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=[O:11].Cl>C(O)C.[Cl-].[Na+].O>[CH3:3]/[C:4](/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:5]\[CH2:6][NH:7][C:8](=[O:15])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CC(=O)NC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CNC(=O)CC(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
Sodium hydroxide (1 N, 0.68 mL, 0.68 mmol) was added to a stirred solution of ethyl 3-[(E,E)-3,7,11-trimethyl-2,6,10-dodecatrienylamino]-3-oxopropionate (0.115 g, 0.34 mmol) in ethanol (2 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 minutes, then warmed to room temperature and stirred for 0.5 hours. The reaction mixture was poured into brine, acidified with hydrochloric acid (5%) and extracted with ethyl acetate. The extract was washed with brine, dried, filtered and evaporated to afford the title compound (80 mg, 0.26 mmol, 76%) as a gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5](=O)[CH:6]([CH3:34])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:22]([N:23]3[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]3)=[CH:21][CH:20]=[CH:19][C:18]=2[CH:30]2[CH2:32][CH2:31]2)=[C:11]([CH3:33])[CH:10]=1)=O)[CH3:2].[NH2:37][NH2:38]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[NH:37][N:38]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[C:22]([N:23]4[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]4)=[CH:21][CH:20]=[CH:19][C:18]=3[CH:30]3[CH2:31][CH2:32]3)=[C:11]([CH3:33])[CH:10]=2)[C:6]=1[CH3:34])=[O:36])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1ccc(OCc2c(C3CC3)cccc2-n2nnn(C)c2=O)c(C)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)c1C

Procedure:
At room temperature, to a mixture of 4-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3-methyl-2,4-dioxo-butyric acid ethyl ester (described in Reference Preparation example 115) 5.5 g, tetrahydrofuran 100 ml was added hydrazine one hydrate 0.56 g and the resulting mixture was stirred for twelve hours. The reaction mixture was concentrated under reduced pressure to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g. Next, the mixture of the above-mentioned 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g, toluene 70 ml and dimethyl sulfate 3.8 g was stirred at 100° C. for three hours. To the reaction mixture was added water and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester 1.4 g (hereinafter, referred to as “Present compound 48”).
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1C[CH2:50][CH2:49][CH2:48]1>>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:40][CH2:50][CH2:49][CH2:48]3)=[O:39])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=1)[CH3:38]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1CCNC1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 809 and pyrrolidine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (33 mg) was obtained.
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[Cl:5][C:6]1[C:12](Cl)=[CH:11][C:9]([NH2:10])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1.O>CN(C=O)C>[Cl:5][C:6]1[C:12]([S:2][CH3:1])=[CH:11][C:9]([NH2:10])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(N)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h

Procedure:
Methyl mercaptan gas was passed into a stirred suspension of 1.16 g (30 mmol) of 60% oil-dispersed NaH in 45 mL of DMF until evolution of H2 gas ceased. 5 g (24 mmol) of 4,5-dichloro-2-nitroaniline (Aldrich) was then added portionwise. After 30 min of stirring, the reaction mixture was poured into 200 mL of water. Yellow precipitate formed was collected by filtration and dried. This gave 3.8 g (72%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ2.5 (s, 3H, CH3), 6.9 (s, 1H, aromatic), 7.6 (br s, 2H, NH2), 8.0 (s, 1H, aromatic)
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:6]=[N:5]1)[C:2]#[CH:3].[BH4-].[Na+].Cl>O1CCCC1>[CH2:1]([N:4]1[CH:8]=[C:7]([CH2:9][CH:10]([C:11]#[N:12])[C:13]#[N:14])[CH:6]=[N:5]1)[C:2]#[CH:3]
Reactant: C#CCn1cc(C=C(C#N)C#N)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1cc(CC(C#N)C#N)cn1
Reaction time: 4 h
Yield: 43.4 %

Procedure:
0.73 g of [(1-propargyl-1H-pyrazol-4-yl)methylidene]malononitrile was dissolved in 10 ml of tetrahydrofuran, and 0.19 g of sodium borohydride was then added under ice-cooling. The mixture was stirred for 4 hours under ice-cooling. The reaction mixture was added to 0.5 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.32 g of [(1-prop-2-ynyl-1H-pyrazol-4-yl)methyl]malononitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH:24]([NH2:26])=[NH:25].CC[O-].[Na+].Cl>C(N1CCC(C(OCC)=O)C(=O)C1)C1C=CC=CC=1.CO.C(Cl)Cl.CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([OH:16])=[N:26][CH:24]=[N:25][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: Oc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 180.5 %

Procedure:
Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (30 g, 101 mmol) was combined with formamidine aceate (10.5 g, 101 mmol) and EtOH (450 mL) in a 2-liter flask. The resulting mixture was stirred at 0° C. and treated with NaOEt (21% in EtOH) (112.6 mL, 299 mmol). The reaction was heated at 60° C. overnight and monitored for completion via 1 cms and TLC (DCM:MeOH:: 95:5). Additional ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (2 g, 6.6 mmol) was added after 12 h with continued heating at 60° C. The reaction was complete after 4 h as indicated by LCMS. The cooled reaction was reduced in vacuo and the residue was treated concentrated HCl (300 mL) and stirred overnight at room temperature. The solvents were removed under vacuum and the resulting solids treated with EtOH (300 mL), stirred for 15 minutes, and then filtered. The mother liquor was discarded and the precipitate dried in a vacuum oven affording 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (44 g) as the tri-HCl salt which was used directly in the next step.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[N:30]3)=[CH:24][CH:23]=2)[C:9]([NH:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2([C:19]([O-:21])=[O:20])[CH2:18][CH2:17]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>C1COCC1.C(O)C>[CH:3]1([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]3[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[N:30]3)=[CH:26][CH:27]=2)[C:9]([NH:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(NCC/C=C/C1(C(=O)[O-])CC1)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCC=CC1(C(=O)O)CC1)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
86 mg (2.15 mmol) of sodium hydroxide were added to a solution of 120 mg (0.215 mmol) of ethyl cis/trans-1-[4-{[(+)-2-cyclopentyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl]amino}but-1-en-1-yl]cyclopropanecarboxylate in 0.23 ml of THF and 0.56 ml of ethanol. The suspension was stirred at RT for 20 min and then acidified slightly with 1 N hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. This gave 112 mg of the target compound as a cis/trans isomer mixture.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1(C)C=CC(S(O[CH2:17][C@H:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[CH3:23][C:20]1([CH3:24])[O:19][C@@H:18]([CH2:17][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:22][O:21]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Temperature: 100 °C
Yield: 95.9 %

Procedure:
A mixture of 4-iodopyrazole (1.40 g, 7.21 mmol), (R)-(−)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (2.27 g, 7.93 mmol), Cs2CO3 (3.52 g, 10.8 mmol) and DMF (10 mL, 100 mmol) was heated to 100° C. for 16 hrs. The reaction mixture was diluted with EtOAc, washed with water (2×), dried with sodium sulfate, filtered and concentrated in vacuo to a solid which was purified using a Teledyne ISCO Combiflash® Rf system [0→20% EtOAc/Heptane] to afford 2.13 g of the title compound (96%). 1H NMR (400 MHz, CDCl3) d 7.55 (s, 1H), 7.52 (s, 1H), 4.43 (dd, J=4.8, 6.1 Hz, 1H), 4.24-4.28 (m, 2H), 4.08 (dd, J=6.3, 8.8 Hz, 1H), 3.76 (dd, J=6.1, 8.6 Hz, 1H), 1.39 (s, 3H), 1.34-1.37 (m, 3H). MS (ESI): m/z 309.01 [M+H]+. UPLC: tR=1.26 min (UPLC-TOF: polar—3 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.ClCCl.C([O-])(=O)C.[K+].[C:38]([O:44][CH2:45][C@H:46]([C:52]1[C:61]([CH3:62])=[CH:60][C:55]2[N:56]=[C:57](Br)[S:58][C:54]=2[C:53]=1[C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=1)[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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.O>[C:38]([O:44][CH2:45][C@@H:46]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:52]1[C:61]([CH3:62])=[CH:60][C:55]2[N:56]=[C:57]([C:2]3[CH:3]=[C:4]4[N:10]([CH3:11])[N:9]=[CH:8][C:5]4=[N:6][CH:7]=3)[S:58][C:54]=2[C:53]=1[C:63]1[CH:64]=[CH:65][C:66]([Cl:69])=[CH:67][CH:68]=1)(=[O:43])[C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cn1ncc2ncc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (20 mg, 0.094 mmol) in dioxane (2 mL) was added bis(pinacolato)diboron (29 mg, 0.113 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (8 mg, 0.0094 mmol), potassium acetate (19 mg, 0.189 mmol). The mixture was degassed and heated at 100° C. for 2 h. The mixture was cooled, and then added (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (25 mg, 0.046 mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol), K2CO3 (33 mg, 0.23 mmol) and water (0.3 mL, degassed). The reaction mixture was heated at 90° C. for 1 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude product which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C32H35ClN4O3S: 591.22 (M+H+); Found: 591.2 (M+H+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[CH3:39][O:40]C1C=C(CC(=O)C(OCC)=O)C=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:40][CH3:39])[CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cccc(OC)c1
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(OC)c1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 62 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-methoxyphenyl)-2-oxopropanoate B9 (100 mg, 0.369 mmol), sodium hydride (11.88 mg, 0.495 mmol) and 2,3,4,6 tetra-O-acetyl-α-D-galactose bromide (185 mg, 0.450 mmol). The resulting compound was isolated in the form of white solid in 62% yield.