Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][NH2:14])[CH:8]=2)[N:3]=1.[CH:15](OC)=[O:16]>>[CH3:1][C:2]1[C:10]([CH3:11])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][NH:14][CH:15]=[O:16])[CH:8]=2)[N:3]=1
Reactant: COC=O
Reactant: CC1=Nc2ccc(CN)cc2C1(C)C
Product: CC1=Nc2ccc(CNC=O)cc2C1(C)C
Yield: 95 %

Procedure:
Aminomethylindole 36 (1.29 g, 6.86 mmol) was dissolved in methyl formate (40 mL) and the mixture was heated at reflux for 2 days. The volatile components were evaporated in vacuo to afford the protected amine 37 as a pale yellow oil (1.40 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:6][N:7]2[CH3:16].[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH3:16]
Reactant: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)c(N)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C)c12
Yield: 97.4 %

Procedure:
A solution of ethyl 5-amino-1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (203 mg, 0.650 mmol) and 1M aq. NaOH (2 mL) in EtOH (5 mL) was stirred at 50° C. for 1 h. The solvent was removed and the residue was dissolved in water. The solution was acidified to pH 7 with 2M HCl and the resulting precipitate was removed by filtration, washed with water, and dried to yield 5-amino-1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (180 mg, 97%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][CH3:19])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Cl-].[CH3:21][O:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][CH3:19])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:21][O:22][CH3:23]
Reactant: CCC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: CCC(C(=COC)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-butanone and methoxymethyltriphenylphosphonium chloride there is obtained 3-(2,4-dichloro-β-ethyl-α-methoxymethylenephenethyl)-pyridine as an isomer mixture in the form of a yellow oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1.[CH3:11][Mg]Br.[BH4-].[Na+].[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH:9]([NH2:10])[CH3:11])=[N:7][CH:8]=1
Reactant: C[Mg]Br
Reactant: COc1cnc(C#N)cn1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cnc(C(C)N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.4 %

Procedure:
To a solution of 5-methoxy-pyrazine-2-carbonitrile (1.0 g, 7.4 mmol) in tetrahydrofuran at −78° C. was added dropwise 1 M methylmagnesium bromide (8.14 ml, 8.14 mmol) and the mixture was stirred for 1 h at 25° C. Sodium borohydride (250 mg, 6.62 mmol) was added at −78° C. and the mixture was allowed to warm to 25° C. Aqueous ammonium chloride was added and after addition of excess potassium carbonate the mixture was extracted 3 times with dichloromethane, solvents were evaporated to give 0.05 g (4%) of crude 1-(5-methoxy-pyrazin-2-yl)-ethylamine. LC/MS (method 5): Rt=1.26 min; m/z=154.15 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[C:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC>ClCCl>[O:20]=[C:6]1[N:5]2[CH2:21][C@H:2]([NH:1][S:29]([CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:31])=[O:30])[CH2:3][C@H:4]2[CH2:8][N:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)Cc3ccccc3)CN12
Reaction time: 12 h
Yield: 66.5 %

Procedure:
(6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step h) (100 mg, 0.33 mmol), phenylmethanesulfonyl chloride (125 mg, 0.66 mmol) and Et3N (0.1 g, 0.99 mmol) were added to dichloromethane (3 mL), and the mixture was stirred for 12 hours. The mixture was directly purified by prep-TLC (DCM/MeOH=30:1) to yield 100 mg (67%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.58-7.55 (m, 2H), 7.43-7.40 (m, 5H), 7.20-7.17 (m, 2H), 4.40-4.37 (m, 1H), 4.29 (s, 2H), 4.05-3.97 (m, 4H), 3.68-3.62 (m, 1H), 2.85-2.81 (m, 1H), 2.11-2.07 (m, 1H), 1.78-1.72 (m, 1H); LC-MS: 456.1 [M+1]+.
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[Cl:29])=[S:20])=[C:14]([OH:30])[C:13]=1[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].N1C=CN=C1>>[Cl:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:14]=1[O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2Cl)c1O
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 50.3 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-chloro-3-fluorophenyl)thiourea (575 mg, 1.32 mmol), tert-butyldimethylsilyl chloride (991 mg, 6.6 mmol) and imidazole (179 mg, 2.64 mmol) were reacted to form the desired product (367 mg, 50%). LC-MS m/z 552.2 (M+).
Reaction SMILES: Br[CH:2]([C:14](=[O:20])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].C(#N)C.C[O-].[Na+].[C:27]([OH:35])(=[S:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[C:27]([S:34][CH:2]([C:14](=[O:20])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(c1cccs1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
As for Example 1, 1-[3-bromo-3-(2-thenoyl)propionyl]-L-proline (0.0085 mole) in 25 ml. of acetonitrile is added to a mixture of 0.015 mole of sodium methoxide and 0.015 mole of thiobenzoic acid in 25 ml. of acetontrile. The mixture is stirred at room temperature for 16 hours, one ml. of acetic acid is added and the solvent removed under reduced pressure. The residue is partitioned between dichloromethane and water containing acetic acid. The organic layer is separated, washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure to give the product of the Example as a pale yellow glass.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:15])=[CH:3][CH:2]=1.CC1C(=CC(=CC=1)N=C=O)[N:19]=[C:20]=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N-:19]=[C:20]=[O:21].[CH:10]1[CH:9]=[C:8]([CH2:7][C:5]2[C:4]([OH:15])=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:13]([OH:14])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Oc1ccccc1Cc1ccccc1O
Agent: [Br-]
Product: [N-]=C=O
Temperature: 175 °C
Reaction time: 3 h

Procedure:
Zero point zero five part by mass of tetrabutylammonium bromide was added to 100 parts by mass of a bisphenol F type epoxy resin (Epiclon 830), and with stirring the mixture was heated to 175° C. Then, 20 parts by mass of toluene diisocyanate were supplied, taking 3 hours, and the mixture was further stirred at 175° C. for 4 hours, to obtain an isocyanate modification product of the bisphenol F type epoxy resin.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:21][C:14]1[CH:13]=[C:12]2[C:17]([C:18]3[CH2:19][CH2:20][NH:8][CH2:9][C:10]=3[N:11]2[CH3:22])=[CH:16][CH:15]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c2c(c3ccc(Br)cc31)CCNC2
Reaction time: 1 h
Yield: 97.6 %

Procedure:
tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.75 g, 4.79 mmol) was dissolved in CH2Cl2 (10 mL) and trifluoroacetic acid (TFA) (10 mL) was added. After stirring for 1 h, the mixture was diluted with methylene chloride (50 mL), washed with saturated Na2CO3 solution, dried over sodium sulfate and concentrated to provide the title compound (1.24 g, 97%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J=1.4 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.3, 1.4 Hz, 1H), 4.01 (s, 2H), 3.55 (s, 3H), 3.15 (t, J=6.0 Hz, 2H), 2.72 (t, J=5.7 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:5]([C:2]4([OH:1])[CH2:4][CH2:3]4)=[O:7])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)C1(O)CC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3(O)CC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-hydroxycyclopropanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (53.4% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 8.03, 7.01, 3.98-3.73, 3.58, 1.53, 1.16, 1.02, 0.76, 0.48, 0.10. MS (ES+) m/z 360 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C(=O)N([I:21])C(=O)C1>ClCCl>[I:21][C:13]1[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: Clc1cc(Cl)cc(-c2cc[nH]n2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Clc1cc(Cl)cc(-c2n[nH]cc2I)c1
Reaction time: 96 h
Yield: 59 %

Procedure:
2.13 g (0.01 mol) of 3-(3,5-dichlorophenyl)pyrazole are dissolved, at room temperature and with stirring, in 50 ml of dichloromethane. 2.5 g (0.011 mol) of n-iodosuccinimide are then added and stirring is then continued for 4 days. The reaction mixture is then concentrated, the solid obtained is washed with heptane and boiled in 100 ml of 1N sodium hydroxide. After cooling, the solid is filtered, washed with water and dried to give 2 g (yield 59%, melting point: 170° C.) of 4-iodo-3-(3,5-dichlorophenyl)pyrazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].C(OC(=O)N[C@H](C)C(N(OC)C)=O)(C)(C)C.COC1C=CC(Br)=CC=1>>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[C:9]([C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Fc1cccc(F)c1Br
Agent: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: COc1ccc(Br)cc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1c(F)cccc1F

Procedure:
With the exception that (S)-t-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate and 1-bromo-2,6-difluorobenzene were used instead of (R)-t-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate and 4-methoxybromobenzene, respectively, the same procedure as in Preparation Example 5-5 was repeated to afford the title compound. 0.26 g (17%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[N:16]1([CH2:15][C@@H:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:3][CH:4]=2)=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: FC(F)(F)CCCBr
Product: O=C(c1ccc(OCCCC(F)(F)F)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except the reaction mixture is stirred at room temperature overnight starting from (4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 1-bromo-4,4,4-trifluorobutane. MS (ES+) 385.2.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:18]([OH:47])[CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:46]=[CH:45][C:26]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:35])[CH2:30][CH2:29]3)=[CH:25][CH:24]=2)[CH:7]=[CH:8][C:9]=1[O:10]CC1C=CC=CC=1)=[O:3].[H][H]>C(O)C.[Pd]>[CH2:37]([NH:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:26]2[CH:45]=[CH:46][C:23]([CH2:22][CH2:21][NH:20][CH2:19][CH:18]([C:6]3[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([C:2](=[O:3])[NH2:1])[CH:5]=3)[OH:47])=[CH:24][CH:25]=2)[CH2:29][CH2:30]1)=[O:35])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNCC(O)c3ccc(OCc4ccccc4)c(C(N)=O)c3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNCC(O)c3ccc(O)c(C(N)=O)c3)cc2)CC1

Procedure:
4-{4-[2-({2-[3-(Aminocarbonyl)-4-(benzyloxy)phenyl]-2-hydroxyethyl}-amino)ethyl]anilino}-N-octyl-1-piperidinecarboxamide was dissolved in ethanol (20 mL) and 10% palladium on carbon added (0.1 g). The mixture was shaken overnight on a Parr apparatus under 50 psi hydrogen, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol) to yield the title compound (0.030 g, 0.05 mmol)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[C:23]#[CH:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: C#CC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester and 1-ethyl-propyl-amine in DMSO was heated at 130° C. overnight. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR(CDCl3) d 8.26(d,1H), 6.87(s,2H), 6.26(s,1H), 4.11(m,1H), 3.87(s,3H), 2.324(m,1H), 2.30(s,3H), 2.17s,3H), 2.08(s,6H), 1.92(q,2H), 1.16(t,3H) ppm.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:13]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[CH:21][CH:20]=1)[C:14]([OH:16])=[O:15]>>[C:3]([S:10][CH:13]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[CH:21][CH:20]=1)[C:14]([OH:16])=[O:15])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(SC(CCc1ccc(-c2ccccc2Cl)cc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To 17.4 ml. of 2N alcoholic potassium hydroxide solution (0.035 mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution is cooled to room temperature and to this is added in small portions 0.035 mole of α-chloro-γ-(2'-chloro-4-biphenylyl)butyric acid. The reaction mixture is stirred at room temperature for 25 hours, then the solvent is removed, the residue dissolved in ether, filtered and washed with cold water. The ethereal solution is then dried over magnesium sulfate and evaporated to dryness to obtain α-benzoylthio-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[NH2:23][C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CN1CCC(N)CC1>C(O)(=O)C>[CH3:24][N:23]1[CH2:3][CH2:2][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CN1CCC(N)CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CN1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 33.8 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 1-methylpiperidin-4-amine (0.124 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 47.3 mg (0.15 mmol, 33.8% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:31])[N:5]([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([N:27]([O:29][CH3:30])C)=[O:26])[C:6]=1[Cl:7].Cl.O(N)C>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:31])[N:5]([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([NH:27][O:29][CH3:30])=[O:26])[C:6]=1[Cl:7]
Reactant: CON(C)C(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: CON
Agent: Cl
Product: CONC(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
Prepared from the product of example 1 part d) and methoxylamine hydrochloride following the procedure of example 1 part e).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:15][CH2:14][CH2:13][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=1>CN1C(=O)CCC1.O>[CH:8]1([C:6]2[N:7]=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:21][CH:22]=3)[C:3]3[CH2:15][CH2:14][CH2:13][C:4]=3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1nc(C2CCCC2)nc2c1CCC2
Reactant: NC(=O)Cc1ccc(N)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)Cc1ccc(Nc2nc(C3CCCC3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 56.4 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.132 g, 0.59 mmol) and (4-aminophenyl)acetamide (0.178 g, 1.18 mmol) in NMP (4 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, diluted with water (40 mL), then extracted with 3:1 chloroform/isopropanol (3×25 mL). The combined extract was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using dichloromethane/methanol (9:1) as eluent followed by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.112 g, 56%) as a light brown solid. MW=336.43. M.p. 228-230° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.51 (s, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.39 (s, 1H), 7.16 (d, J=8.5 Hz, 2H), 6.82 (s, 1H), 3.10 (quin, J=8.0 Hz, 1H), 2.77 (q, J=9.0 Hz, 4H), 2.01 (quin, J=7.5 Hz, 2H), 1.98-1.90 (m, 2H), 1.87-1.78 (m, 2H), 1.78-1.68 (m, 2H), 1.65-1.55 (m, 2H); APCI MS m/z 337 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8].CN(C=O)C>O>[N:1]([CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8])=[N+:2]=[N-:3]
Reactant: O[C@@H](CCl)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H](O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
Sodium azide (41.8 g, 642 mmol) was added to a solution consisting of (1R)-2-chloro-1-(4-fluoro-phenyl)-ethanol (37.4 g, 214 mmol) and DMF (214 mL) at rt. The reaction mixture was heated to 100° C. for 3 h, diluted with water (500 mL), and extracted with EtOAc (700 mL). The organic layer was washed with brine (500 mL), and the organic layer dried (MgSO4), filtered, and concentrated, giving the title compound as a yellow liquid, which was used without further purification (39 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[NH:6][C:5](=[O:7])[CH:4]([NH:8]C(=O)OC(C)(C)C)[CH2:3]1.[ClH:17].O1CCOCC1>C(Cl)Cl>[ClH:17].[NH2:8][CH:4]1[CH2:3][C:2]([CH3:16])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)CC(NC(=O)OC(C)(C)C)C(=O)N1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)CC(N)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl N-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)carbamate (which may be prepared as described in Description 28) (1307 mg, 5.73 mmol) in DCM (5 mL) was added 4 M HCl in dioxane (2.86 mL, 11.45 mmol). The solution (which immediately started to evolve gas) was stirred at room temperature over 1 hour. The reaction mixture heavily precipitated. It was diluted with ether (approximately 50 mL) and the solid filtered under vacuum, washed with ether and dried in the vacuum oven to afford 3-amino-5,5-dimethyl-pyrrolidin-2-one hydrochloride (917 mg, 5.5701 mmol, 97.3% yield) as a white solid;
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH3:23][C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][C:7]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3cc(CO)ccc3C)c(=O)n(C)c2n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CSc1ncc2cc(-c3cc(C=O)ccc3C)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.9 %

Procedure:
6-(5-Hydroxymethyl-2-methyl-phenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (129 mg, 0.394 mmol) was dissolved in 7 mL methylene chloride at room temperature, and MnO2 (343 mg, 3.94 mmol) was added. The reaction mixture was stirred for 48 hours at room temperature, then filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC plate, eluting with 5% MeOH/DCM, to give 73 mg of 4-methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzaldehyde, MS (M+H)=326.
Reaction SMILES: [Na].[CH:2]([CH:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])=O.[Cl-].[CH3:12][NH2+:13][CH3:14].C(Cl)(Cl)Cl>O>[CH3:12][N:13]([CH:2]=[C:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])[CH3:14]
Reactant: C[NH2+]C
Reactant: N#CC(C=O)CNC=O
Agent: [Cl-]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C=C(C#N)CNC=O

Procedure:
98.6 parts of 75 percent pure sodium salt of α-formyl-β-formylaminopropionitrile and 81.5 parts of dimethylammonium chloride in 700 parts by volume of chloroform are refluxed for 1.5 hours, during which time 8.5 parts (theory: 9 parts) of water are eliminated. The mixture is filtered, the filtrate is concentrated to dryness and the product is recrystallized from methanol. 43.0 parts of α-dimethylaminomethylene-β-formylaminopropionitrile of melting point 90° C. are obtained.