Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1S[C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[NH2:15])=O)C.[CH:16]([NH2:18])=O.CC([O-:23])(C)C.[K+]>[NH4+].[Cl-]>[N:15]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[O:23][C:6]=2[C:4]([OH:3])=[N:18][CH:16]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1sc2c(c1N)CCCC2
Reactant: NC=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Product: Oc1ncnc2c3c(oc12)CCCC3
Temperature: 110 °C

Procedure:
A 15 mL flask was charged with 3-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid ethyl ester (synthesized by the route described in Example 5, Step A; 0.50 g, 2.4 mmol), formamide (4.8 mL), and KOtBu (95%; 0.56 g, 4.8 mmol) under N2. After heating at 110° C. for 12 h, the mixture was poured over cold satd. aq. NH4Cl (10 mL). Filtration afforded the desired product (0.31 g). MS: No signal. 1H NMR (400 MHz, d6-DMSO) δ ppm 8.00 (s, 1H), 2.74-2.69 (m, 2H), 2.56-2.51 (m, 2H), 1.92-1.81 (m, 2H), 1.79-1.69 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:33])(=[O:32])[NH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[F:31])[N:15]=2)[CH2:8][CH2:7]1)C.[BH4-].[Li+]>C1COCC1>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:16]1[N:15]=[C:14]([NH:13][S:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][OH:3])[CH2:7][CH2:8]2)(=[O:33])=[O:32])[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CCN(CCO)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of {4-[2-(2,3-Difluoro-benzylsulfanyl)-6-methoxy-pyrimidin-4-ylsulfamoyl]-piperazin-1-yl}-acetic acid ethyl ester (the product from example 86 step i) (0.31 g) lithium borohydride (1M solution in THF (1.2 mL) in THF (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and NH4OAc/acetonitrile as the mobile phase) then titurated with Toluene, MeOH followed by DCM to give the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17]CC)=O.C(N(CC)CC)C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C(O)C>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:15]([C:3]2[N:4]=[C:5]3[N:10]([C:11](=[O:12])[C:2]=2[OH:1])[CH2:9][CH2:8][O:7][C:6]3([CH3:13])[CH3:14])=[O:17])=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 35 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
Additional procedure. Ethyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (50 g, 0.186 mol) and ethanol SDA3A (500 mL) was added to a 1 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet-outlet, temperature probe, and condenser. Triethylamine (18.86 g, 0.186 mol) was added to the slurry. The resulting solution was heated to 35° C. followed by slow addition of 4-fluorobenzylamine (35.0 g, 0.279 mol). The thick slurry was heated at 78° C. with stirring for 6 h. The reaction mixture was polish filtered and the filtrate reheated to 70° C. The pH was adjusted to about 1.0 by slow addition of 1N HCl (405 mL). The thick slurry was cooled to 20–25° C., the solids filtered off, washed twice with ethanol SDA 3A (each 250 mL) and twice with water (each 500 mL). The white solid was dried in vacuo at 50–55° C. to afford N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide (58.9 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O[C@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([O:30][C@@H:32]2[CH2:37][CH2:36][O:35][C:33]2=[O:34])[CH:27]=[CH:28][CH:29]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Reactant: O=C1OCC[C@@H]1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN(Cc2cccc(O[C@@H]3CCOC3=O)c2)c2nc3ccccc3o2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
In an argon atmosphere, N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (2.0 g), (S)-2-hydroxybutyrolactone (1.0 g), and triphenylphosphine (2.6 g) were dissolved in toluene (30 mL), and a solution of di-tert-butyl azodicarboxylate (2.3 g) in toluene (10 mL) was dropwise to the solution at 0° C., followed by stirring for 24 hours at 40° C. Subsequently, triphenylphosphine (1.3 g) and di-tert-butyl azodicarboxylate (1.1 g) were added to the mixture at 40° C., followed by stirring for 24 hours at the same temperature. The reaction mixture was returned to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. The washed mixture was dried over sodium sulfate anhydrate. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=1/1), to thereby yield a colorless oil (2.2 g, 92%, 98% ee).
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6](=[O:11])([O:8][CH2:9][CH3:10])[NH2:7]>COC1C=CC(O)=CC=1.C(Cl)(Cl)Cl>[CH3:4][CH:3]([CH2:2][NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[CH:5]([NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11]
Reactant: CCOC(N)=O
Reactant: C=C(C)C=O
Agent: COc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCC(C)C(NC(=O)OCC)NC(=O)OCC
Reaction time: 1 h
Yield: 60.8 %

Procedure:
35 g of methacrolein are added dropwise at 60°-65° C. to a mixture of 133.5 g of ethyl carbamate, 30 g of acid ion exchanger resin (Duolite C 265), 0.4 g of hydroquinone monomethyl ether and 400 ml of chloroform in the course of 40 minutes. The mixture is left at that temperature for 1 hour, the ion exchanger is filtered off, the chloroform is distilled off, and the residue is crystallized from ethyl acetate/petroleum ether. This gives 97 g of 2-methyl-1,1,3-tri(ethoxycarbonylamino)propane (60.8% yield, based on starting methacrolein) having a melting point of 138°-140° C.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:19][I:20]>CC(C)=O>[I-:20].[CH2:12]([N+:7]1([CH3:19])[CH2:8][CH2:9][C:10](=[O:11])[CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CI
Reactant: CCCCC1CN(Cc2ccccc2)CCC1=O
Solvent: CC(C)=O
Product: CCCCC1C[N+](C)(Cc2ccccc2)CCC1=O
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a solution of 3-butyl-1-benzyl-piperidine-4-one (9080 mg) in acetone (40 ml) was slowly added methyl iodide (6303 mg) at room temperature. The solution was stirred at room temperature for three hours. A white solid precipitated and was filtered off. The solid was washed four times with 50 ml of acetone and dried under reduced pressure. The filtrate was evaporated and the residue was stirred with ethyl acetate. The white solid was filtered, washed with ethyl acetate and dried under vacuum. The two solids were combined to yield 1-benzyl-3-butyl-1-methyl-4-oxo-piperidinium iodide as a white powder (11200 mg). MS (ESI): 204.2 (M−1−).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH2:14][OH:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH2:14][O:15][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OCc1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1ccc(Cl)cc1Cl
Yield: 89.3 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 2,4-dichlorobenzyl alcohol, the titled compound was obtained as a white solid. (Yield: 89.3%)
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1)[CH2:2][CH2:3][CH3:4].[CH2:15]([Br:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br-:22].[CH2:15]([N:7]1[CH:8]=[CH:9][N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]1[CH:10]1[O:11][CH2:12][CH2:13][O:14]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCn1ccnc1C1OCCO1
Reactant: BrCc1ccccc1
Product: CCCC[n+]1ccn(Cc2ccccc2)c1C1OCCO1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
A reaction mixture of 19.3 g (104 mmol) of 1-butyl-2-(1,3-dioxolan-2-yl)imidazole and 17.75 g (104 mmol) of benzyl bromide was stirred at room temperature for 24 h. The mixture was triturated with ethyl aceate, decanted and dried to afford 35.3 g of 3-benzyl-2-(1,3-dioxolan-2-yl)-1-butyl-imidazolium bromide (Formula VI: A=1-butylimidazole; Y=2-(1,3-dioxolan-2-yl); R1 =R6 =H; Z- =Br-).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17][CH2:16]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COc2cccc(OCC3CCNCC3)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCC(COc2cccc(OCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{[3-(Benzyloxy)phenoxy]methyl}piperidine hydrochloride (1.5 g) was dissolved in chloroform (30 mL), and diisopropyl ethylamine (3.13 mL) and methanesulfonyl chloride (0.52 mL) were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was powdered and purified from chloroform/hexane to obtain 4-{[3-(benzyloxy)phenoxy]methyl}-1-(methylsulfonyl)piperidine (1.508 g).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:22](=O)([O-])[O-:23].[K+].[K+]>O>[OH:23][CH2:22][N:9]1[C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:10]1=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: C=O
Agent: [K+]
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 g of 5,5-diphenylhydantoin (0.08 moles) and 80 ml (32 g) of formalin are introduced into a suitable reaction vessel containing 720 ml of water and one g of potassium carbonate. The reaction is stirred at room temperature for 24 hours, after which the subject compound, mp 186.5°-188.5° C., yield 22.58 g (91.86%) is obtained by filtration.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].Cl.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][Cl:14])[N:12]=1>Cl>[ClH:14].[ClH:1].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[N:12]=1
Reactant: Nc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Product: NCCSCc1csc(N)n1

Procedure:
Cysteamine hydrochloride (5.65 g; 50.0 mmoles) and 2-amino-4-chloromethylthiazole hydrochloride (9.25 g; 50.0 mmoles) were dissolved in 70 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 105°. After 64 hours of heating the mixture was evaporated under reduced pressure and the residue triturated with acetone. The collected product was re-triturated with ethanol, filtered and dried to yield the title compound, mp 170°-200°.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:21])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+].Cl>CO>[Br:21][C:15]1[CH:16]=[C:17]([N+:18]([O-:20])=[O:19])[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:22])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)CC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 75.6 %

Procedure:
To a suspension of 1.00 g (2.69 mmol) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in a 1:1 mixture of water:methanol (50 mL) is added 2.0 mL (5.0 mmol) of sodium hydroxide as a 10% aqueous solution. The mixture is heated at 60° C. for 1 hour then cooled to room temperature and the pH of the mixture is adjusted to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.700 g (75.7%) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid as an orange oil. No further purification is performed.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.Cl[C:16]([O:18][CH3:19])=[O:17].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:19][O:18][C:16]([N:6]1[CH:7]([C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][CH:21]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:17]
Reactant: COC(=O)Cl
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: c1ccc2[nH]ccc2c1
Product: COC(=O)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
6-(1H-Indol-3-yl)-6H-phenanthridine-5-carboxylic acid methyl ester was prepared from phenanthridine, methyl chloroformate, and indole according to GP 2. Yield, 9%. (+)-ESI-MS: m/z=355 [M+H]+, 238 [M-indole+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:14][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: Cc1cnc(F)cc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2ccc(Cl)cc2)c(CBr)cn1

Procedure:
A mixture of EXAMPLE 307A (1.2 g), N-bromosuccinimide (1.06 g) and AIBN (azobisisobutyronitrile) (0.178 g) in CCl4 (30 mL) was heated under reflux for 6 hours. After cooling, the solid was filtered off. The filtrate was concentrated and loaded onto a silica gel column eluting with 3% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][O:21][C:22]([CH2:24][C:25]#[N:26])=[O:23].[ClH:27]>C(OCC)C>[ClH:27].[CH3:20][O:21][C:22]([CH2:24][C:25](=[NH:26])[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: COC(=O)CC#N
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOC(=N)CC(=O)OC
Reaction time: 48 h
Yield: 46.8 %

Procedure:
In a mixture of 27.0 parts of stearyl alcohol in 200 volume parts of dry ethyl ether and 9.9 parts of methyl cyano acetate was introduced about 5.3 parts of dry hydrogen chloride gas at room temperature, followed by keeping at room temperature for 2 days. The resulting white precipitates were washed with ethylether and dried to give 19.0 parts of stearyl methoxycarbonylacetimidate hydrochloride melting at 83° to 85°C (decomposition). Yield: 46.8%
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[C:5]([F:17])[CH:4]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1)[CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][N:18]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Reactant: Cn1cc(-c2ccc(CN)cc2F)ccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(CNC(=O)c3ccc(-c4cnccn4)cc3)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the 5-(4-(aminomethyl)-2-fluorophenyl)-1-methylpyridin-2(1H)-one 21-7 (obtained in Step 4), 4-(pyrazin-2-yl)benzoic acid 18-3 (5.0 mg, 0.025 mmol), and HATU (9.5 mg, 0.025 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to give N-(3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-4-(pyrazin-2-yl)benzamide 21 (2.5 mg). MS m/z 415.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:32][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.[Cl-:39]>ClCCl.C(OCC)C>[ClH:39].[CH3:30][O:29][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]3[CH2:9][NH:8][CH2:32][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:11]=3[N:12]=2)[CH:22]=[CH:21][C:20]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: [Cl-]
Reactant: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CN(C(=O)OC(C)(C)C)C3)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CNC3)ccc1-n1cnc(C)c1
Product: Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-8-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert.-butyl ester (75 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added at 0° C. 2M hydrogene chloride (0.73 mL) in diethyl ether. The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure to yield the title compound (70 mg, 100%) as a yellow solid. MS ISP (m/e): 413.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.01 (m, 2H), 9.23 (s, 1H), 8.57 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.26-7.38 (m, 6H), 7.15 (d, 1H), 4.56 (dd, 1H), 4.37 (m, 2H), 3.64 (m, 1H), 3.42 (m, 1H), 3.38 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=N[CH:7]=1.F[C:12]1C(B(O)O)=CC=CN=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>O1CCOCC1.O.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>[NH:8]1[C:5]2[CH:12]=[CH:7][CH:2]=[N:3][C:4]=2[CH:10]=[CH:9]1
Reactant: OB(O)c1cccnc1F
Reactant: Brc1cnc2[nH]ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: c1cnc2cc[nH]c2c1
Temperature: 140 °C
Yield: 137.7 %

Procedure:
To a 25 mL microwave vial was added 2-bromo-5H-pyrrolo[2,3-b]pyrazine (0.5 g, 2.52 mmol), 2-fluoropyridin-3-ylboronic acid (600 mg, 4.26 mmol) and sodium carbonate (803 mg, 7.57 mmol) in dioxane (10.0 ml), water (5.00 ml), and EtOH (2.5 ml). The reaction mixture was bubbled through with argon for 10 mins. Pd(PPh3)4 (292 mg, 0.252 mmol). The reaction was bubbled through with argon for 5 mins. The vial was capped and heated in the microwave at 140° C. for 15 min. The reaction mixture was diluted with EtOAc and water. The combined organics were separated, dried (MgSO4), filtered and concentrated. The crude residue dissolved in DCM and treated with silica. The solvent was evaporated and the crude absorbed in silica was purified by SiO2 chromatography eluting with EtOAc/hexane gradient (0% to 60%) to afford 410 mg (76%) of pyrrolopyridine as a light yellow solid. MS m/z (ES): 215 (M+H)+.
Reaction SMILES: O1CCCCC1O[CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[NH:24]1C2C(=CC(OC3CCC(O)CC3)=CC=2)C=N1>>[NH:20]1[C:21]2[C:17](=[CH:16][C:15]([O:14][C@H:11]3[CH2:12][CH2:13][CH2:8][C@H:9]([NH2:24])[CH2:10]3)=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: c1cc2[nH]ncc2cc1OC1CCC(OC2CCCCO2)CC1
Reactant: OC1CCC(Oc2ccc3[nH]ncc3c2)CC1
Product: N[C@H]1CCC[C@H](Oc2ccc3[nH]ncc3c2)C1

Procedure:
The following compound of Example 384 was synthesized by carrying out reactions according to the methods described in Example 372, (b) and Example 381, except for using the cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 323, (c), as a starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[CH3:14]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:11][CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 3-chloro-4-nitrothiophenol (3.3 g) in N,N-dimethylformamide (5 ml) was added dropwise to an ice-cooled mixture of 60% sodium hydride (0.7 g) in N,N-dimethylformamide (10 ml). The mixture was stirred at 0° to 5° C. for 1 hour. To the above mixture was added dropwise methyl iodide (3.7 g) at 5° C. The mixture was stirred at room temperature for 1 hour, poured into ice-water (80 ml), and extracted with toluene. The extract was dried and evaporated. The oily residue was crystallized from a mixture of hexane and ethanol to give crystals of 3-chloro-4-nitrothioanisole (2.8 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]([CH2:38][CH3:39])[CH2:40][CH3:41])=[CH:17][N:16]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: CCN(CC)CCC(=O)Nc1cnc(N)c2c(-c3ccc(N)c(OC)c3)csc12
Product: CCN(CC)CCC(=O)Nc1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-Amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-diethylaminopropionamide, and the procedure described in General Procedure F. m/z (M+H)+571.3.