Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[N:24]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])[N:24]=2)=[CH:21][CH:22]=1
Reactant: Nc1nccc(-c2ccc(Cl)cc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 112b) from 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 4-(4-chloro-phenyl)-pyrimidin-2-ylamine. The title compound was obtained as a colorless solid (Yield=35%). MS ISP (m/e): 387.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.31 (s, 1H), 8.69 (d, 1H), 8.47 (s, 1H), 8.25-8.15 (m, 3H), 7.97 (s, 1H), 7.55-7.50 (m, 3H), 7.57 (d, 1H), 7.29 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:26])[N:14]([CH3:25])[N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]=1S(C)=O)[CH3:2].CN1CCCC1=[O:33].[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:26])[N:14]([CH3:25])[N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]=1[OH:33])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C(F)(F)F)nn(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C(F)(F)F)nn(C)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
To a 30 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-39) (0.375 g), N-methylpyrrolidone (3.49 g), water (1.75 g), and sodium hydroxide (0.34 g) were added at room temperature. The resulting mixture was stirred at 50° C. for 4 hours. Then, the resulting mixture was cooled to room temperature, added 12N hydrochloric acid (1.5 ml) and water (15 ml), and extracted with ethyl acetate (30 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane:ethyl acetate=7:1 to hexane:ethyl acetate=5:1 to hexane:ethyl acetate=3:1) to give 0.147 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2-methyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((1-16)-(1)-39).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:11][CH2:12][CH2:13][CH2:14][O:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: BrCCCBr
Reactant: Oc1ccc2scnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: BrCCCOc1ccc2scnc2c1
Reaction time: 8 h
Yield: 30.2 %

Procedure:
A mixture of intermediate 25 (1 g, 6.6 mmol), 1,3-dibromopropane (1.83 mL, 18 mmol), anhydrous K2CO3 (828 mg, 6.0 mmol) and EtOH (20 mL) was heated to reflux and stirred overnight. The yellow solid was filtered and purified by column chromatography (elution with PE/EtOAc=3:1) to afford 5-(3-bromopropoxy)benzo[d]thiazole (intermediate 27) (543 mg, 33%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:27])=[C:20]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:27][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:26])[C:23](=[O:25])[CH3:24]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)c(C)nn23)ccc1F
Yield: 74.9 %

Procedure:
A mixture of 0.046 g (0.38 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 92 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 75%).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:27])=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19]([OH:21])=O)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1>>[C:35]([N:32]1[CH2:33][CH2:34][CH:29]([NH:28][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([CH3:27])=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)[C:11]=3[NH:18][CH:17]=2)=[O:21])[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CC(=O)c1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1C
Product: CC(=O)c1cc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c(OCC2CC2)cc1C

Procedure:
Starting from 4-(5-acetyl-2-cyclopropylmethoxy-4-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A82) and 1-(4-amino-piperidin-1-yl)-ethanone (A191) the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH:30]=O)=[CH:24]3)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:20][CH2:19][CH2:18][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:29][CH:28]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of 5-bromo-2-oxindole (46 mg, 0.22 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.22 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (64%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:27]>ClCCl>[CH:14]1([N:13]([CH:17]2[CH2:19][CH2:18]2)[C:11]([C:9]2[N:8]([CH2:20][CH3:21])[C:6]3=[N:7][C:2]([N:1]=[C:26]=[S:27])=[C:3]4[N:24]=[CH:23][N:22]([CH3:25])[C:4]4=[C:5]3[CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a mixture of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 194.5 mg, 0.575 mmol) in dichloromethane (2874 μL) in a round bottom flask under nitrogen was added 1,1′-thiocarbonyldi-2(1H)-pyridone (133 mg, 0.575 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. N,N-Dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (180 mg, 94% yield) was isolated as a yellow sticky solid. The material was used as is in subsequent reactions.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=O)[CH:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(Cl)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (5.0 g, 18 mmol) and phosphoryl chloride (8.2 mL, 90 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (4.73 g, 88%). MS (ISP) 298.2 [(M+H)+] and 300 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Br:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Br:15])=[C:10]([Br:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Br)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Br)c(Br)s2)c1Br
Yield: 45 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dibromothiophene-2-sulphonyl chloride in 45% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153-155° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:24])[CH:7]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C>C1(C)C=CC=CC=1>[F:20][C:19]([F:22])([F:21])[C:18]([NH:17][C:7]1[C:6](=[O:24])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1)=[O:23]
Reactant: CC(C)CNC(=O)C(CC(=O)c1ccccc1)NC(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)CN1C(=O)C(NC(=O)C(F)(F)F)=CC1c1ccccc1
Yield: 87.1 %

Procedure:
A solution of N-isobutyl-4-oxo-4-phenyl-2-[(trifluoroacetyl)amino]butanamide (0.500 g, 1.45 mmol) and acetic acid (0.831 mL, 14.5 mmol) in toluene (15 mL) was heated to reflux. After 48 hours the reaction was cooled and concentrated. The crude product was purified by chromatography (silica gel, 0 to 50% ethyl acetate in hexane gradient elution) to give the title compound as a solid (0.412 g). MS 327 (M+1) 1H NMR (500 MHz, CDCl3) □ 7.40-7.36 (m, 3H), 7.20 (d, J=2.0 Hz, 1H), 7.12-7.11 (m, 2H), 5.12 (d, J=2.0 Hz, 1H), 3.53 (dd, J=13.9, 9.4 Hz, 1H), 2.61 (dd, J=13.9, 5.9 Hz, 1H), 1.89-1.80 (m, 1H), 0.87 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2c(Br)ccc(O)c21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2c(Br)cc([N+](=O)[O-])c(O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
4-Bromo-7-hydroxyindan-1-one (3.06 g, 13.5 mmol) was suspended in acetic acid (20 mL), and acetic anhydride (1.66 mL, 17.6 mmol) and fuming nitric acid (838 μL, 20.2 mmol) dissolved in acetic acid (10 mL) were added. The mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give the title compound (2.98 g, yield 79%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][C:18]([CH3:26])([CH3:25])[CH2:19][C:20]([O:22]CC)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][C:18]([CH3:26])([CH3:25])[CH2:19][C:20]([OH:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(C)Cc1nc2ccccc2n1Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CC(=O)O)Cc1nc2ccccc2n1Cc1ccccc1
Yield: 64 %

Procedure:
9 g of ethyl 4-(1-benzylbenzimidazol-2-yl)-3,3-dimethylbutanoate, prepared in Example 47, are dissolved in a mixture composed of 90 ml of concentrated hydrochloric acid, 270 ml of water and 250 ml of acetic acid. The mixture is refluxed for 4 hours and the solvents are concentrated under vacuum. The residue is taken up with a 1N solution of sodium hydroxide and the resulting mixture is washed with ether; the aqueous phase is acidified by having sulfur dioxide bubbled through it until the pH is 5-6, and the crystals formed are filtered off and washed with water and isopropyl ether to give 5.3 g of 4-(1-benzylbenzimidazol-2-yl)-3,3-dimethylbutanoic acid in the form of crystals melting at 160°-1° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:20]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>O>[OH:30][CH2:29][CH2:31][NH:32][C:2]1[N:3]=[C:4]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[N:10]=[C:9]([NH:32][CH2:31][CH2:29][OH:30])[N:8]=[C:7]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:20]=1
Reactant: Clc1nc(NCc2ccccc2)c2nc(Cl)nc(NCc3ccccc3)c2n1
Reactant: NCCO
Solvent: O
Product: OCCNc1nc(NCc2ccccc2)c2nc(NCCO)nc(NCc3ccccc3)c2n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A mixture of 2,6-dichloro-4,8-di-(benzylamino)pyrimidopyrimidine (0.32 g, 0.78 mmol) and ethanolamine (2 ml) was stirred at 150° C. for 12 h. The reaction mixture was cooled to room temperature and water (15 ml) was added, after which the mixture was stirred for a further 20 min, filtered, washed with water, and the collected solid dried in vacuo. Purification by silica column chromatography (dichloromethane: methanol, 9:1) yielded the title compound (0.11 g, 31%) as a fluorescent yellow solid (Found: C, 61.0; H, 6.0; N, 23.7. C24H28N8O2.0.14CH2Cl2 requires C, 61.4; H, 5.6; N, 23.2); NMR data was as follows:
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1)[CH3:14]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[NH:25][CH2:24][CH2:23][S:22][CH2:21][C:19]1[O:20][C:16]([CH2:15][N:13]([CH3:14])[CH3:12])=[CH:17][CH:18]=1)([O-:7])=[O:6]
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of the product of Step A is reacted with about an equimolar amount of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine to give, after workup and chromatography as in Example 1, the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])[CH2:12]3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:14][C@H:13]3[C@@H:9]2[CH2:10][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])[CH2:12]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)N1C[C@@H]2C[C@@H](c3ccc(Cl)cc3)[C@@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)N1C[C@H]2C[C@H](c3ccc(Cl)cc3)[C@H]2C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Example 48A (0.44 g, 1.4 mmol) in methanol (4 mL) and water (4 mL) was added 5 N aqueous NaOH solution (1.4 mL, 7.1 mmol). After stirring at 60° C. for 16 hours, the reaction mixture was cooled, neutralized to pH˜7 with 3 N HCl, and concentrated to obtain crude 2-[(1S,5R,6S)-6-(4-chlorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]-2-methylpropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=S)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=[N:30][CH2:29][CH2:28][CH2:27][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1
Reactant: NCCCn1ccnc1
Reactant: S=C1c2cccc3cccc(c23)N1Cc1ccc(Cl)cc1
Solvent: CCO
Product: Clc1ccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1
Yield: 34 %

Procedure:
A mixture of 2.5 g of 1-p-chlorophenylmethylbenz[cd]indole-2(1H)-thione (Cp), 1.1 g of 1H-imidazole -1-propanamine, 200 ml of ethyl alcohol, and 2.6 g of mercuric acetate is reacted as described in Example 3, giving 1.1 g of the desired product, mp. 90°-91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.C1C=C(O[C:30](OC2N=CC=CC=2)=[S:31])N=CC=1>>[N:1]([C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1)=[C:30]=[S:31]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CNc1nccc(-c2ccccc2Oc2ccc(N)cc2)n1
Product: CNc1nccc(-c2ccccc2Oc2ccc(N=C=S)cc2)n1
Reaction time: 8 h

Procedure:
To a slurry of 4-(2-(4-aminophenoxy)phenyl)-N-methylpyrimidin-2-amine (0.300 g, 1.03 mmol) in MC was added di-2-pyridyl thionocarbonate (0.227 g, 0.977 mmol). The orange reaction was allowed to stir overnight, and was then diluted with MC and washed 4×H2O. The organic layer was dried over anhyd. Na2SO4, filtered, and concentrated in vacuo to give 4-(2-(4-isothiocyanatophenoxy)phenyl)-N-methylpyrimidin-2-amine as an off-white solid. This material was used without further purification. MS m/z=335 [M+H]+. Calc'd for C18H14N4OS: 334.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][OH:8].[C:9]([C:11]1([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:13][CH2:12]1)#[N:10]>CCO>[CH3:18][C:17]([CH3:20])([S:15]([NH:14][C:11]1(/[C:9](=[N:7]/[OH:8])/[NH2:10])[CH2:13][CH2:12]1)=[O:16])[CH3:19]
Reactant: CC(C)(C)S(=O)NC1(C#N)CC1
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)S(=O)NC1(/C(N)=N/O)CC1
Temperature: 60 °C
Yield: 96.3 %

Procedure:
Potassium carbonate (4.45 g, 32.2 mmol) and hydroxylamine hydrochlordie (1.1 g, 16 mmol) was added to a stirring solution of N-(1-cyanocyclopropyl)-2-methylpropane-2-sulfinamide (1.5 g, 8.1 mmol) in EtOH (27 ml) at rt. The reaction was heated to 60° C. for 2 h. Then the reaction was allowed to cool to rt. Celite was added and the mixture was filtered through a pad of celite washing with 100 mL of EtOAc. The filtrate was concentrated to give the expected product (Z)-1-(1,1-dimethylethylsulfinamido)-N′-hydroxycyclopropanecarboximidamide (1.7 g, 7.8 mmol, 96% yield) consistent by LCMS. LC-MS retention time: 1.09 min; m/z (MH+): 220. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][C:6]([CH3:8])=[N:5][N:4]([CH3:9])[C:3]1=[O:10].[C:11]1([C:17]2[N:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:9][N:4]1[C:3](=[O:10])[N:2]([NH:1][C:23]([C:20]2[CH:19]=[N:18][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:22][CH:21]=2)=[O:24])[CH2:7][C:6]([CH3:8])=[N:5]1
Reactant: CC1=NN(C)C(=O)N(N)C1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=NN(C)C(=O)N(NC(=O)c2cnc(-c3ccccc3)nc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 54.6 %

Procedure:
To a solution of 4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.219 g, 1.58 mmol) and 2-phenyl-pyrimidine-5-carboxylic acid (0.317 g, 1.58 mmol) in dry DMF (10 mL) under N2 is added DMTMM (0.46 g, 1.66 mmol). The mixture is stirred at rt for 22 h, then diluted with EtOAc (70 mL), and washed successively with saturated aqueous NaHCO3 solution (2×10 mL) and brine (10 mL). The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with heptane:EtOAc gradient to afford 2-phenyl-pyrimidine-5-carboxylic acid (2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-amide as a solid (0.28 g, 55%). MS: 325 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 2H), 8.45 (dd, J=7.7, 2.0 Hz, 2 H), 7.52-7.62 (m, 3H), 4.25 (s, 2H), 3.18 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(F)cc1Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
Methyl bromoacetate (36.33 g, 0.24 mol) is added to a mixture of o-(5-fluoro-2-nitrophenoxy)phenol (39.45 g, 0.16 mol) and potassium carbonate (32.75 g, 0.24 mol) in N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 18 hours, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow solid (42 g) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:16]([CH:17]=[CH:18][C:4]1[C:3]2[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]=1[C:12]([O:14][CH3:15])=[O:13])=[O:19]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COC(=O)C=Cc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
In 23 ml of anhydrous acetonitrile were dissolved 1.5 g (7.4 mmol) of methyl 4,7-dimethylindole-2-carboxylate and 7.6 ml of methyl acrylate. The air in the reaction system was substituted with nitrogen. After cooling the reaction mixture to 0° C., 1.66 g (7.4 mmol) of palladium acetate was added and the reaction mixture was stirred for 30 minutes. Stirring was further continued at room temperature for 19 hours. After addition of 60 ml of acetonitrile, the reaction mixture was subjected to Celite filtration. The filtrate was concentrated under reduced pressure and the solids thus obtained were purified by silica gel column chromatography to provide 680 mg of yellow crystals. Yield: 48%