Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:16][CH:15]=[N:14][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:27]Br>CN(C=O)C>[Br:27][C:11]1[O:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:18]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)Nc1ncnc2occ(-c3ccc([N+](=O)[O-])cc3)c12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncnc2oc(Br)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 0° C. solution of Example 27A (350 mg, 0.98 mmol) in DMF (10 mL) was treated with Br2 (0.102 mL, 1.98 mmol), warmed to room temperature, and stirred for 1 hour. The reaction was cooled to 0° C., quenched with 1:1 10% NaHSO3/saturated NaHCO3, and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide 400 mg (93%) of the desired product. MS (ESI(−)) m/e 433, 435 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[F:18][C:19]([F:43])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:42])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:14]([F:15])([F:17])[F:16])[CH:4]=3)[CH2:9][CH2:10]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([N:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:34]=[N:35][N:36]([CH3:39])[C:37]=4[CH3:38])[CH2:28][CH2:27]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1>CN(C=O)C>[CH3:39][N:36]1[C:37]([CH3:38])=[C:33]([CH2:32][N:29]2[CH2:28][CH2:27][N:26]([C:21]3[C:20]([C:17]4[CH:16]=[CH:15][C:14]([CH2:13][N:3]5[CH2:8][CH2:7][CH2:6][CH2:5][C:4]5=[O:9])=[CH:19][CH:18]=4)=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:31][CH2:30]2)[CH:34]=[N:35]1
Reactant: O=C1CCCCN1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CCl)cc3)CC2)cnn1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN4CCCCC4=O)cc3)CC2)cnn1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Add sodium hydride (0.175 g of 60% weight suspension in mineral oil; 2.62 mmol) to a solution of piperidin-2-one (0.270 g; 2.73 mmol) in DMF (5 mL). Cool the mixture to 5° C., stir for 30 min., remove the cooling bath, warm to room temperature and stir for 30 min. Add 3′-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.253 g; 0.540 mmol) in 6 mL of DMF and stir for 20 hr. at room temperature. Quench with a solution of 10% aq. acetic acid (9 mL), add methanol (minimal volume to achieve a homogeneous solution) and add to a 5 gm SCX column (Varian; pre-rinsed with MeOH). Elute the crude product with 2 M ammonia in methanol (18 mL) and concentrate. Purify via chromatography on silica gel eluting 0-10% methanol/DCM to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-piperidin-2-one (0.180 g; 73%). MS (ES+) m/z: 460 (M+H)+. Purify by high pH reverse phase HPLC, and concentrate to give the free base. Dissolve the free base in acetonitrile and convert to the hydrochloride salt by adding 1 eq. 2 M aq. HCl solution. Add water and lyophilize to give the title compound as a brown powder (164 mg, 66%). MS (ES): m/z=460 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([C:5]2[C:6]([C:8]3[C:13]([F:14])=[CH:12][N:11]=[C:10]4[NH:15][CH:16]=[CH:17][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:19][CH:20]=1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2c(F)cnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 using 4-[1-ethyl-4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and ethyl isocyanate afforded the title compound. ESMS [M+H]+: 393.4
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9](OC)=[O:10]>CO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([NH:1][NH2:2])=[O:10]
Reactant: COC(=O)c1cncc(Cl)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cncc(Cl)c1
Temperature: 70 °C
Yield: 50 %

Procedure:
Hydrazine (17.93 mg, 0.560 mmol) was added to methyl 5-chloronicotinate (80 mg, 0.466 mmol) in methanol (8 mL) and heated overnight at 70° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the compound was purified by column chromatography affording the title compound (40 mg). 1H NMR (400 MHz, CD3OD): δ 8.85 (d, 1H, J=2.0 Hz), 8.70 (d, 1H, J=2.4 Hz), 8.22 (t, 1H, J=2.0 Hz). ESI-MS: 172.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-])=O)[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:1][CH:2]([CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CNCc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CNCc1ccccc1N
Reaction time: 8 h

Procedure:
A mixture of (±)-2-Methyl-3-((2-nitro)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (80 mg), ammonium chloride (53 mg), and zinc powder (106 mg) in 6 ml of EtOH—H2O (9-10) was stirred overnight, and then filtered through a layer of zeolite. The filtercake was rinsed with methanol (5 ml×3), and the combined filtrate was concentrated under reduced pressure. The residue was then partitioned between of dichloromethane and saturated aq. sodium bicarbonate (6 ml each). The aqueous layer was then extracted with dichloromethane (6 ml). The organic layer was washed with brine and then concentrated to yield (±)-2-Methyl-3-((2-amino)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide as a resin: MS (m+1)=460.3; 1H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 1.15 (dd, 3H), 2.00 (m, 1H), 2.25 (m, 2H0, 2.60 (q, 1H), 2.70 (q, 1H), 2.90 (m, 1H), 3.05 (m, 1H), 3.10 (m, 1H), 3.20 (q, 1H), 3.35 (q, 1H), 3.45 (q, 1H), 3.70 (m, 2H), 4.25 (m, 2H), 4.35 (m, 2H), 4.55 (m, 2H), 6.6-7.2 (m, 4H), 6.8-7.0 (m, 2H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidin-2-yl}-benzenesulfonamide (example 262) (0.480 g, 0.912 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.25 g, 46%). MS (ISP) 469.3 [(M+H)+]; mp>250° C.
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][OH:28])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:29]1[CH2:31][CH:30]1[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>CN(C)C=O>[OH:29][CH:30]([C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1)[CH2:31][O:28][CH2:27][C:25]1[N:24]=[CH:23][N:22]([C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:26]=1
Reactant: N#Cc1ccc(C2CO2)cc1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
20.0 mmol of sodium hydride (60% dispersion in paraffin) are added to a solution of 20.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-02] in 120 ml of absolute N,N-dimethylformamide under argon. The mixture is heated at 100° C. for 1 hour and then cooled to 40° C. A solution of 20.0 mmol of 4-oxiranylbenzonitrile [52695-39-3] in 10 ml of absolute N,N-dimethylformamide is added dropwise at 35-40° C., and the reaction mixture is stirred at 40° C. for 15 minutes. The reaction mixture is cooled to room temperature, poured into ice-water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over sodium sulphate and evaporated. The title compound is obtained as a white solid from the residue by flash chromatography (SiO2 60 F). Rf=0.29 (dichloromethane-methanol 95:5); Rt=4.26 (gradient I).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=2)[NH:3]1.[N:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[C:35]3[C:30](=[CH:31][C:32]([CH:36]=O)=[CH:33][CH:34]=3)[NH:29][N:28]=2)=[CH:21][CH:20]=1>>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:36]\[C:32]1[CH:31]=[C:30]3[C:35]([C:27](/[CH:26]=[CH:25]/[C:22]4[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=4)=[N:28][NH:29]3)=[CH:34][CH:33]=1)=[CH:8][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:6][CH:5]=2
Reactant: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Yield: 75.4 %

Procedure:
The title compound (102 mg, 76%) was synthesized as orange-yellow solid according to the method described for Example A11B from tert-butyl 2-oxoindolin-5-ylcarbamate (70 mg, 0.282 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (70 mg, 0.282 mmol). 1H NMR (400 MHz, d6-DMSO) δ 13.53 (s, 1H), 10.47 (s, 1H), 9.14 (s, 1H), 8.55 (d, J=6.5 Hz, 2H), 8.33 (d, J=8.8 Hz, 1H), 7.88-7.83 (m, 3H), 7.74 (s, 2H), 7.69 (d, J=6.5 Hz, 2H), 7.56-7.50 (m, 2H), 6.75 (d, J=8.2 Hz, 1H), 1.34 (s, 9H); MS ESI 480.3 [M+H]+, calcd for [C28H25N5O3+H]+ 480.20.
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:22])(=[O:21])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1.Cl.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29]Cl>C(O)C>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:21])(=[O:22])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5]1
Reactant: CN(C)CCCCl
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CN(C)CCCn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1

Procedure:
Sodium (0.69 g) was dissolved in ethanol (45 ml) and 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (4.68 g) was added. 3-Dimethylaminopropyl chloride hydrochloride (2.37 g) was added to the mixture, which was then stirred and boiled under reflux for 2.5 hr. On cooling some solid separated, which was filtered off and discarded. Overnight yellow crystals of 3-(2-(3-dimethylaminopropyl)-5-tetrazolyl)thioxanthone-10,10-dioxide separated and were filtered off and recrystallised from ethanol, m.p. 141°-142° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:14])[CH:12]=[CH2:13]>C(#N)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:13][CH2:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNCC1
Reactant: C=CC(=O)OCc1ccccc1
Solvent: CC#N
Product: CC(=O)NC1CCN(CCC(=O)OCc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A stirred mixture of 4-acetamidopiperidine (1.82 g, 12.8 mmol) and benzyl acrylate (2.57 g, 15.4 mmol) in acetonitrile (50 mL) was stirred overnight under nitrogen and at 40° C. for 1 h. The mixture was evaporated to dryness and the residue was purified by silica gel chromatograph eluting with a gradient of 0% to 30% dichloromethane/methanol/NH4OH (10:1:0.1) and dichloromethane to give benzyl 3-(4-acetamidopiperidin-1-yl)propanoate as an oil (3.81 g, 98%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].O>ClCCl>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CC(C)(O)CN
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Under a nitrogen atmosphere, 1-amino-2-methylpropan-2-ol (25.5 g, 0.28 mol) was added over a period of 30 minutes to a solution of 4-chloro-3-nitro[1,5]naphthyridine (54.5 g, 0.26 mol) in dichloromethane (1 L). A water bath was used to control the exotherm and maintain the temperature of the reaction at or below 27° C. The reaction mixture was stirred at ambient temperature overnight. The resulting precipitate (crop 1) was isolated by filtration. The filtrate was concentrated under reduced pressure to provide crop 2. The two crops were slurried separately with de-ionized water for 2 hours and then isolated by filtration. Crop 1: 40.53 g of 2-methyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-2-ol as a yellow solid. Crop 2: tan solid. Crop 2 was dissolved in dichloromethane and loaded onto an alumina column. The column was eluted first with 1% methanol in dichloromethane and then with acetone. The combined eluents were concentrated under reduced pressure. The residue was recrystallized from ethanol (10 mL/g) to provide 6.95 g of 2-methyl-1-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-2-ol.
Reaction SMILES: CN(C)C=O.Cl.[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1.[OH-].[K+].[F:19][C:20]([F:24])=[C:21]([F:23])[F:22]>O>[Cl:14][C:13]1[CH:12]=[C:11]([O:15][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])[C:10]([Cl:16])=[CH:9][C:8]=1[NH2:7]
Reactant: Nc1cc(Cl)c(O)cc1Cl
Reactant: FC(F)=C(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)F)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 100 ml dimethylformamide (DMF), 75 g (0.035 mole) 4-amino-2,5-dichlorophenol, hydrochloride, and 3.0 g (0.05 mole) KOH (pellets ground to powder) was placed in a 500 ml 3-necked round bottom flask fitted with a mechanical stirrer, thermometer and reflux condenser and was stirred for about 1 hour. It was then heated to 85° C. with stirring and 6.0 g (0.06 mole) of tetrafluoroethylene was bubbled in while heating at 85°-90° C. The addition took about 10 minutes. The reactor and contents were cooled in an ice water bath and 200 ml of water were added. The product was extracted with 200 ml methylene chloride and then again with 100 ml methylene chloride. The extracts were combined and the solvents removed by vacuum distillation. A residue (7 g) remained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12](C(OC(C)(C)C)=O)/[C:11](=[C:26]3/[C:27]([CH3:39])=[N:28][N:29](C(OC(C)(C)C)=O)[C:30]/3=[O:31])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[CH3:39][C:27]1=[N:28][NH:29][C:30](=[O:31])/[C:26]/1=[C:11]1\[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:3][CH:4]=3)=[CH:10]\1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CC1=NN(C(=O)OC(C)(C)C)C(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NS(C)(=O)=O)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-tert-butyl 4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)quinoline-1 (2H)-carboxylate and methanesulfonyl chloride according to the procedure described in Example 21. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H) 3.09 (s, 3H) 6.69 (s, 1H) 7.44 (d, J=8.59 Hz, 2H) 7.63 (t, J=7.58 Hz, 1H) 7.72 (d, J=8.59 Hz, 2H) 7.83-7.94 (m, 2H) 8.13 (d, J=8.34 Hz, 1H) 10.40 (s, 1H); ESI-MS: m/z calc'd for C20H18N4O3S2 426.08. found 427.3 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:2]([OH:4])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: COCn1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCn1ccnc1C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
At a temperature of -10° C., 27.5 g. (0.25 mol) of ethyl chloroformate was added drop-wise to a solution of 28 g. (0.25 mol) of 1-(methoxymethyl)imidazole and 25 g. (0.25 mol) of triethylamine in 125 ml. of anhydrous chloroform. The mixture was stirred at 0° C. and then kept standing for two days at room temperature. The precipitated triethylamine hydrochloride was filtered off and washed with diethyl ether. The filtrate was concentrated by evaporating the solvents and the residue was dissolved in diethyl ether. The solution was dried over sodium sulphate, the ether was distilled off and the residue was distilled. The ethyl ester of 1-(methoxymethyl)imidazole-2-carboxylic acid was obtained. Boiling point 120°-124°/2 mm. Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N:4][C:3]=1[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>O1CCCC1.[Pd]>[CH3:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][CH:2]=[C:3]([CH2:13][CH2:14][CH3:15])[N:4]=1
Reactant: CCCc1nc(C)c(C(=O)OC)nc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cnc(C(=O)OC)c(C)n1
Reaction time: 8 h

Procedure:
To a solution of methyl 6-chloro-3-methyl-5-propylpyrazine-2-carboxylate (3.00 g, 13.1 mmol) and triethylamine (1.83 mL, 13.1 mmol) in tetrahydrofuran (40 mL) was added palladium on carbon (5%, M, wet, 300 mg) at 0° C. under argon. The reaction mixture was stirred for 8 h under hydrogen atmosphere, and then filtrated through celite with tetrahydrofuran. To the filtrate was added manganes dioxide (1.0 g) at room temperature. After being stirred overnight, the reaction mixture was filtrated through celite with tetrahydrofuran. The filtrate was concentrated in vacuo, and the residue was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 13:7) to give methyl 3-methyl-5-propylpyrazine-2-carboxylate. MS (APCI): m/z 195 (M+H).
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][C:5]1[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CCOCC>[CH3:4][C:5]1[C:10]([C:11]([OH:13])([CH3:1])[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1cccnc1C
Agent: [Br-]
Solvent: CCOCC
Product: Cc1ncccc1C(C)(C)O
Temperature: 25 °C
Yield: 61.9 %

Procedure:
MeMgBr (3.0 M in Et2O, 4.63 ml, 13.9 mmol) was added dropwise via syringe to a solution of 1-(2-methyl-pyridin-3-yl)-ethanone (1.88 g, 13.9 mmol) (Sanders et al. J. Org. Chem. 1978, 43, 324) in Et2O (60 mL) to give a white slurry. The mixture was refluxed for 16 h, cooled to room temperature, quenched with water (50 mL) and extracted with CH2Cl2 (7×60 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) afforded 2-(2-methyl-pyridin-3-yl)-propan-2-ol as a white crystalline solid (1.30 g, 62%). 1H NMR (CDCl3) δ 1.67 (s, 6H), 2.79 (s, 3H), 7.08 (m, 1H), 7.75 (d, 1H, J=7.5 Hz), 8.36 (d, 1H, J=3.0 Hz).
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O.CCOCC>[Si:8]([O:6][CH:4]([CH3:5])[CH2:3][CH:2]([OH:7])[CH3:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(O)CC(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O)CC(C)O[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a solution of 1.00 g (9.60 mmol) 2,4-pentanediol in 9 mL dimethylformamide was added 1.52 g (10.1 mmol) t-butyldimethylsilyl chloride and 915 mg (13.4 mmol) imidazole. The solution was stirred for 12 hrs, diluted in 100 mL of ether, and washed 5×, each with 2 mL water. The organic phase was dried over MgSO4, filtered, and concentrated. Chromatography on a 2×18 cm column, packed with hexane and eluted with 100 mL each of 5%, 10%, and 25% ethyl acetate/hexane provided 1.192 g of a clear colorless oil in 10 mL fractions 6-14.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:3]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23]([CH3:24])=[O:33])[N:18]=1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(c1cccc2c1ccn2-c1ccnc(SC)n1)S(C)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCN(c1cccc2c1ccn2-c1ccnc(S(C)=O)n1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
N-ethyl-N-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanesulfonamide (0.4 g) in CHCl3 (60 mL) was cooled to 0° C. and MCPBA (0.247 g) added and stirred at 0° C. for 5 h before quenching with 10% sodium thiosulfate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified on a column using 100% DCM to 15% MeOH/DCM to yield N-ethyl-N-[1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanesulfonamide (0.386 g).