Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(OCC)(=O)C>CS(C)=O>[CH3:13][C:4]1[CH:3]=[C:2]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: NCc1ccccn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(NCc2ccccn2)c2cccc(O)c2n1
Temperature: 160 °C
Yield: 43.9 %

Procedure:
A mixture of the 4-chloro-2-methylquinolin-8-ol (2.00 g, 10.3 mmol) and 2-aminomethyl pyridine (3.35 g, 30.9 mmol) in DMSO (5 mL) was heated at 160° C. for 2 h under nitrogen atmosphere. The mixture was cooled, poured into ice/NaHCO3 and extracted with ethyl acetate and dichloromethane. Evaporation gave a crude mixture that was mixed with ethyl acetate. The yellow solid precipitated and was filtered and dried to give 1.20 g of 2-methyl-4-((pyridin-2-ylmethyl)amino)quinolin-8-ol (44%). MS (+APCI) 266 (M+). 1H-NMR (CDCl3, δ): 8.56 (m, 1H), 7.79 (t, J=6.0 Hz, 1H), 7.75 (dt, J=2.0, 7.6 Hz, 1H), 7.63 (dd, J=1.2, 8.4 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.25 (m, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.29 (s, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([NH2:20])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3].[C:25](Cl)(Cl)=[O:26].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([N:20]=[C:25]=[O:26])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3]
Reactant: O=C(Cl)Cl
Reactant: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)N(C)CC=C)c1I
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C=CCN(C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)CC=C)c1I
Temperature: 60 °C

Procedure:
To a solution of N,N′-diallyl-5-amino-2,4,6-triiodo-N,N′-dimethyl-isophthalamide (5 g, 7.5 mmol) in 1,4-dioxane (10 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (35 mL, 70 mmol) at ambient temperature, the solution was heated at 60° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off white, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:14][CH3:15].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.O>CN(C=O)C>[CH2:14]([C:6]1[N:7]([CH2:41][C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:2])=[O:16])[CH3:15]
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide ((91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+ 377)
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH:11]1[N:24]([CH3:25])[C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1>C(N(CC)CC)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH:35]([C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)[CH:36]2[CH2:41][CH2:40][N:39]([CH2:9][CH2:10][CH:11]3[N:24]([CH3:25])[C:16]4=[N:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:15]4[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]3)[CH2:38][CH2:37]2)=[CH:43][CH:44]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CC(CCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)N(C)c2nc3ccccc3n2C1=O
Reaction time: 24 h

Procedure:
To a solution of 50 mL of toluene containing 4.0 g (0.04 mol) of triethylamine was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one and 4.0 g (0.014 mol) of 4-[bis(4-fluorophenyl)methyl]piperidine. The mixture was heated to reflux for 3 days after which time 1.0 g (0.003 mL) of 4-[bis(4-fluorophenyl)methyl]piperidine and 1.0 g (0.01 mol) of triethylamine was added. Heating under reflux was continued for 24 hr. The solvent was removed by rotary evaporation and the residue dissolved in 100 mL of CH2Cl2. The organic phase was washed with 2×100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was subjected to preparative HPLC using silica gel as the stationary phase and eluting with ethanol. Combination of like fractions afforded 3.1 g (57%) of analytically pure material as a glass.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16]O)[CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16][Cl:25])[CH:3]=1
Reactant: N#Cc1cnc(Nc2cc(CO)cc(Cl)n2)s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(CCl)cc(Cl)n2)s1

Procedure:
2-{[6-Chloro-4-(hydroxymethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile 11-7 (0.132 g, 0.49 mmol) was stirred in anhydrous CH2Cl2 (2 mL) under N2. N,N-Dimethylformamide (0.038 mL, 0.49 mmol) was added followed by the addition of phosphorous oxychloride (0.046 mL, 0.49 mmol). After 2.5 hours the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford 2-{[6-chloro-4-(chloromethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile as a yellow solid. 1H NMR (DMSO-d6) δ 12.63 (bs, 1H), 8.34 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H), 4.82 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[F:13][C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1.Cl>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([CH:3]2[C:2](=[O:1])[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=3)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: O=C1Cc2ccccc2S1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 40 ml of tetrahydrofurane is added dropwise, at 10° to 20°, to a stirred suspension of 1.93 g of a 50% strength sodium hydride/mineral oil suspension in 50 ml of tetrahydrofurane. The mixture is stirred for a further 30 minutes at room temperature and 5.5 g of 3-fluoro-phenyl isocyanate are then added slowly dropwise, an exothermic reaction taking place. The reaction mixture is then stirred for a further one hour at room temperature and for one hour at 40° and is poured into a mixture of 500 ml of ice water and 50 ml of 2 N hydrochloric acid and the precipitate, which at first is oily but immediately crystallises, is filtered off and recrystallised from acetone/petroleum ether. N-(3-Fluorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide with a melting point of 169°-171° is obtained.
Reaction SMILES: [O:1]1[C@@H:3]2[C@H:4](O)[C@@H:5]3[C@@H:14]([C@@:15]4([CH3:27])[CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][C@@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[C@@H:7]2[CH2:29][C@@H:8]2[C:9]1=[O:28].[Cl:31]CCl.ClC(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1>[Cl:31][C@@H:4]1[C@H:3]2[O:1][C@:2]32[C@:15]([CH3:27])([CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19]3)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:28])[C@H:8]2[CH2:29][C@@H:7]12
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 169 g of 5,6β-epoxy-7β-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one in a mixture of respectively 340 ml of dichloromethane, tetrachloromethane, and pyridine is combined with 200 g of triphenylphosphine and stirred for 2 hours at room temperature. The reaction solution is washed with water, dried over sodium sulfate, and evaporated to dryness under vacuum. The residue is stirred up with 310 ml of ethanol and filtered. The filter cake is washed with 175 ml of ethanol and dried under vacuum, thus obtaining 139.2 g of 7α-chloro-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one. An analytical sample, recrystallized from acetone-hexane, has a melting point of 228° C. [α]D =-100° (chloroform).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[NH:26][CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11].Br[CH2:30][CH2:31][C:32]#[N:33]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[N:26]([CH2:30][CH2:31][C:32]#[N:33])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: N#CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CCC#N
Temperature: 10 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and (S)—N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (0.542 mmol, 200 mg) were dissolved in DMF (2 ml). The mixture was cooled to ˜10° C. with an ice bath and 3-bromopropionitrile (0.813 mmol, 109 mg) was slowly added. The reaction mixture was allowed to warm to RT and it was stirred overnight. The liquids were, evaporated. DCM was added and washed twice with water. The separated organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 73.1 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 2.38 (s, 3H), 3.02 (t, 2H), 4.22 (t, 2H), 4.24-4.47 (m, 3H), 6.95 (d, 1H), 7.61 (s, 1H), 7.83 (d, 1H), 7.96-8.02 (m, 2H), 8.07-8.13 (m, 2H).
Reaction SMILES: C[C@@:2]([OH:14])([C@@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](N)=[O:4].[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>>[NH2:13][C@@H:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:2]([OH:14])[C:3]([O:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:4]
Reactant: CC(C)CO
Reactant: C[C@](O)(C(N)=O)[C@@H](N)c1ccccc1
Product: CC(C)COC(=O)[C@H](O)[C@@H](N)c1ccccc1

Procedure:
To a mixture of crude (2R, 3S)-2-hydroxy-3-amine-3-phenylpropionamide (CVII, EXAMPLE 6, 180 mg, 1 mmol) in isobutyl alcohol (2.5 ml) is bubbled anhydrous hydrogen chloride gas until saturated allowing the temperature to rise. The reaction mixture is then heated to 100° overnight. The resulting solution is evaporated to dryness under house vacuum at 50°. The residue is dissolved in water (5 ml), and the aqueous is neutralized with saturated potassium carbonate solution to pH >9. The basic aqueous is extracted with ethyl acetate (15 ml×3). The combined organic phase is dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue is purified by flash chromatography (methanol/dichloromethane, 1/5) to give the title compound, NMR (300 MHz, CDCl3) 7.44-7.28, 4.34, 4.30, 4.00, 1.95 and 0.95 δ; CMR (300 MHz, CDCl3) 173.5, 142.3, 128.5, 127.5, 126.7, 75.0, 71.8, 58.0, 27.6 and 18.9 δ; MS (m/z) 238 (M+ +1), 165, 136, 118, 107, 106, 104, 91, 79, 77 and 57; HRMS (m/z) calculated for C13H19N1O3 +H1 =238.1443, observed=238.1441.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24](O)=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:25])[N:22]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)N3CCN(C)CC3)cs2)c(C(=O)C2CCCC2)c1

Procedure:
4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-acetyl)-1-methyl-piperazine (337 mg) is prepared from 2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)ureido]-thiazol-4-ylacetic acid (386 mg, 1.0 mmol) and N-methylpiperazine following the general procedure K.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O.[Na+].[Cl-].C(O[Ti](OCC)(OCC)OCC)C>[C:14]([S@@:17]([N:19]=[C:4]([C:3]([CH3:12])([CH3:11])[CH2:2][F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CCOC(=O)C(=O)C(C)(C)CF
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)C(C)(C)CF
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
To a solution of ethyl 4-fluoro-3,3-dimethyl-2-oxobutanoate (2.3 g, 13.05 mmol) in THF (20 mL) was added (S)-2-methylpropane-2-sulfinamide (1.899 g, 15.67 mmol) and tetraethoxytitanium (5.91 mL, 26.1 mmol). The reaction mixture was heated at 65° C. for 6 h. The reaction mixture was cooled down, diluted with EtOAc and sat. NaCl (40 mL) and stirred at rt for 0.5 h. The solid was filtered and washed with water and EtOAc. The filtrate was separated and the organic layer was washed with water, sat. NaCl, dried (MgSO4) and purified by flash chromatography (EtOAc/hexane) to afford (S)-ethyl 2-(tert-butylsulfinylimino)-4-fluoro-3,3-dimethylbutanoate (1.1 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.46-4.53 (1H, m), 4.28-4.42 (3H, m), 1.59 (3H, s), 1.21-1.31 (15H, m).
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[CH:11]=O.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>CC(O)=O>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:3]3[N:2]([CH3:1])[C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cn1c(C=O)cc2ccccc21
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cc4ccccc4n3C)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1-methyl-1H-indole-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 390.3 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1>C(=S)=S>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: BrBr
Reactant: COc1ccc(O)cc1
Solvent: S=C=S
Product: COc1ccc(O)c(Br)c1
Yield: 57.1 %

Procedure:
A solution of 2.6 mL (100 mMol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes to a solution of 12.4 gm (100 mMol) 4-methoxyphenol in 20 mL carbon disulfide at 0° C. After 30 minutes an additional 1 mL of bromine in 10 mL carbon disulfide are added dropwise. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in diethyl ether. This solution was washed sequentially with 100 mL water and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 11.6 gm (57%) of the desired compound as a crystalline 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])[C:5]2=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(O)(=O)C>CO>[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=[N:18]\[C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2/C1=N/c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 392.3 %

Procedure:
A mixture of 5-bromo-1H-indole-2,3-dione (1.0 g, 0.442 mmol) and 3-trifluoromethylaniline (0.993 g, 6.2 mmol) in a solution of 1% acetic acid in methanol was stirred at 50° C. for 12 h. The crude product was concentrated in vacuo, giving the desired crude product (640 mg, 40%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:2].[I:9]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[I:9][C:5]1[S:6][CH:7]=[CH:8][C:4]=1[NH:3][CH:1]=[O:2]
Reactant: O=CNc1ccsc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)(Cl)Cl
Product: O=CNc1ccsc1I
Temperature: 2.5 °C
Yield: 90.5 %

Procedure:
3-Formylamino-thiophene (21 g), N-iodosuccinimide (37.2 g) and tetrachlormethane (200 ml) were refluxed together for 3 hours. The reaction mixture was cooled to 0-5° C. and filtered. The solids were dissolved in ethyl acetate, washed three times with sodium hydroxide (10% solution), washed with brine and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel (hexane:ethyl acetate 2:1) yielded 37.8 g of product (m.p. 100-107° C.) which was directly used in Step B.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2)=[O:21]>C1COCC1>[O:31]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][CH:30]=[C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])[CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.802 g, 4.67 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by distillation. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (0.905 g, 3.59 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (1.05 g, 2.73 mmol, 76%).
Reaction SMILES: N1C=CC=C([C:7]([C:9]2[C:10]([C:15](OC)=O)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])C=1.O.[NH2:20][NH2:21]>C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[C:15]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:7](=[O:8])[NH:21][N:20]=1
Reactant: NN
Reactant: COC(=O)c1ncccc1C(=O)c1cccnc1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccccn2)c2ncccc12
Temperature: 75 °C
Yield: 135.4 %

Procedure:
A mixture of methyl 3-picolinoylpicolinate 7, (240 mg, 0.99 mmol), hydrazine hydrate (63 μL, 1.3 mmol) and 12 mL of absolute ethanol was heated to 75° C. in a sealed tube for 1 h. After cooling, the solid was collected by vacuum filtration and dried under air suction. The mother liquor was concentrated to dryness under reduced pressure and purified by normal phase flash chromatography eluting with 0-10% methanol in dichloromethane over approximately 20 minutes. Like fractions were combined and concentrated under reduced pressure and combined with the solid collected by filtration to give 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one 9 (150 mg, 0.67 mmol). 1H NMR (400 MHz, Methanol-d4) δ 9.07 (dd, J=4.5, 1.6 Hz, 1H), 8.98 (dd, J=8.4, 1.6 Hz, 1H), 8.72 (ddd, J=4.9, 1.7, 1.0 Hz, 1H), 8.00 (ddd, J=7.9, 7.3, 1.7 Hz, 1H), 7.99-7.92 (m, 1H), 7.97-7.84 (m, 1H), 7.53 (ddd, J=7.3, 4.9, 1.5 Hz, 1H). LCMS: (M+H)+, 225.