Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)#[N:13].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[Cl:11][C:4]1[N:3]=[C:2]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,6-Dichloro-3-nitropyridine (II-1, 193 mg, 1 mmol) and p-cyanophenylamine (III-1, 236 mg, 2 mmol) were dissolved in N,N-dimethylformamide (DMF, 3 mL). While cooling in ice bath, potassium t-butoxide (224 mg, 2 mmol) was added in batch, followed by reacting at room temperature for 2 h. The reaction solution was poured into ice water, and adjusted with diluted HCl to a pH of 5-6, followed by stirring for 30 min, to precipitate a solid. The solid was filtered out, washed with water until neutral, dried, and separated via a silica gel column (dichloromethane as eluant), to obtain compound IV-1 (186 mg, 68%), a pale yellow solid, mp 175-178° C. 1H NMR (CDCl3) δ 10.47 (1H, br s, NH), 8.53 (1H, d, J=8.4 Hz, ArH-4), 7.86 (2H, d, J=8.8 Hz, ArH-2′, 6′), 7.70 (2H, d, J=8.8 Hz, ArH-3′, 5′), 6.96 (1H, d, J=8.4 Hz, ArH-5); MS (m/z): 275 (M+).
Reaction SMILES: N1(C[CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.ClCC[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:27]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]#[N:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCN3CCCC3)cc2)CCOCC1
Yield: 59.2 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (570 mg, 2.82 mmol), 1-(2-chloro-ethyl)-pyrrolidine (300 mg, 2.25 mmol), DMF (5.7 ml) and K2CO3 (1.56 g, 1.13 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude material was subjected to chromatography on silica eluting with 5% MeOH in DCM and gradient to 10% MeOH in DCM to provided the title compound (400 mg, 47%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.95 (d, 2H), 4.13 (t, 2H), 4.10-4.03 (m, 2H), 3.89 (td, 2H), 2.92 (t, 2H), 2.64 (br s, 4H), 2.15-1.99 (m, 4H), 1.88-1.76 (m, 4H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=O)[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[S:26])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1CCCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cccc2c1CCCC(=S)N2
Yield: 135.5 %

Procedure:
A suspension of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-one (50 mg, 0.23 mmol) and Lawesson reagent (65 mg, 0.16 mmol) in 3 mL of toluene was refluxed for about 1 h. The residue obtained after evaporation of the solvent was chromatographed on silica gel PTLC (5% MeOH--CH2Cl2) to give 51 mg (94%) of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-thione; MS 235.
Reaction SMILES: [O:1]1[C@@H:9]2[C@H:10]3[C@H:14]([C@H:2]1[C@@H:3]1[C@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1)[C@H:13]([CH3:15])[O:12][C:11]3=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[OH:1][C@H:2]1[C@@H:14]2[C:10]([C:11](=[O:16])[O:12][C@H:13]2[CH3:15])=[CH:9][C@@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: C[C@@H]1OC(=O)[C@H]2[C@H]3O[C@H]([C@H]4CCCC[C@H]43)[C@@H]21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1OC(=O)C2=C[C@H]3CCCC[C@@H]3[C@@H](O)[C@H]21
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To 110.0 mg(0.50 mmol of (3S,3aS,4R,4aS,8aR,9S, 9aR)-4,9-epoxy-3-methyl-decahydronaphtho[2,3-c]furan-1(3H)-one in 20 ml of dehydrated tetrahydrofuran solution were added dropwise 2.50 ml(5 equivalents) of lithium bis(trimethylsilyl)amide-tetrahydrofuran solution (1M) at −78° C. (internal temperature) under an atmosphere of argon, and the mixture was stirred for about 4 hours while raising temperature naturally. At −40° C., 2 ml of saturated aqueous solution of ammonium chloride were added, which was stirred at room temperature, and solvent was distilled off under reduced pressure. To the residue was added 10 ml of water, which was extracted with ether(5 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=2:1) to obtain 100.9 mg of (3S,3aS,4R,4aS,8aR)-4-hydroxy-3-methyl-3a,4,4a,5,6,7,8,8a-octahydronaphtho[2,3-c]furan-1(3H)-one (yield 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[C:3]=1[NH:20][CH2:21][CH:22]([OH:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl.C(N=C=NCCCN(C)C)C.O1CCCC1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH:22]([OH:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(O)CNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(O)Cn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N)c21
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
Under nitrogen atmosphere, a mixture of methyl 4-{[2-amino-6-({[(2,4-dichlorophenyl)amino]carbonothioyl}amino)phenyl]amino}-3-hydroxybutanoate (Reference Example 81; 1.42 g, 3.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.84 g, 9.60 mmol) and tetrahydrofuran (30 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient to give the title compound as an oil (790 mg, 1.93 mmol, 60%).
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][NH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH3:27][S:24]([N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:33]5[C:29]([CH3:28])=[N:30][NH:31][CH:32]=5)[C:10]=4[N:9]=[N:8]3)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)N1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1n[nH]cc1-c1cccc2c1nnn2-c1ccnc(NC2CCN(S(C)(=O)=O)CC2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 149.7 %

Procedure:
A mixture of [4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine (250 mg), 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg) and Na2CO3 (2 M aq, 0.7 mL, degassed), toluene (9 mL, degassed) and EtOH (0.7 mL) was added to a screw cap pressure flask. To this was added Pd(PPh3)4 (20 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was then cooled to RT, and additional portions of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Pd(PPh3)4 (20 mg), and EtOH (5 mL) added. The flask was again sealed and heated overnight at 110° C. The reaction mixture was then diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a solid (0.34 g). The solid was chromatographed on silica, eluting with 0-60% Magic Base/DCM, then chromatographed again on silica using 0-60% Magic Base/DCM. The product was titurated with Et2O, filtered, and dried in vacuo overnight to provide (1-methanesulfonyl-piperidin-4-yl)-{4-[4-(3-methyl-1H-pyrazol-4-yl)-benzotriazol-1-yl]-pyrimidin-2-yl}-amine (Compound 10, 39 mg). Mp=231-232° C.; M+H=454.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:2].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[O:2]1[CH2:11][CH2:12][O:13][CH:1]1[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: OCCO
Reactant: N#Cc1cccc(C=O)c1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C2OCCO2)c1
Yield: 74.9 %

Procedure:
To a solution of 3-formyl-benzonitrile (2 g, 15.25 mmol, 1 eq) in dry toluene (30 mL), paratoluenesulfonic acid (262 mg, 1.5 mmol, 0.1 eq) and ethylene glycol (12.8 mL, 228 mmol, 15 eq) were added and the mixture was heated to reflux in a Dean-Stark apparatus overnight. The toluene was concentrated and the reaction mixture purified by flash chromatography (EtOAc/cHex) to afford the title compound as a colorless liquid (2000 mg, 74%). 1H NMR: (CDCl3, 300 MHz) δ 7.78 (m, 1H), 7.69 (m, 1H), 7.64 (m, 1H), 7.48 (t, J=7.7 Hz, 1H), 5.81 (s, 1H), 4.08 (m, 4H). HPLC (Method A) Rt: 2.45 min (purity: 92.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[OH:12].C(Cl)Cl.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:17](=[O:20])[CH:18]=[CH2:19])=[CH:6][C:5]=1[OH:12]
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc(O)c(C(=O)OC)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester, was added DCM and triethylamine. This mixture was cooled to 0° C. and acryloyl chloride was added dropwise with stirring. After approximately 2 hours, the reaction was quenched by adding MeOH at 0° C. and the resulting mixture was stirred at room temperature for about 15 min and then concentrated in vacuo. DCM and water were added to the residue and this mixture was mixed thoroughly. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed in vacuo to give 4-acryloylamino-5-chloro-2-hydroxybenzoic acid methyl ester. This ester was then combined with Preparation 1, followed by the addition of a THF-MeOH solvent. The mixture was heated and stirred for about 16 hours to provide biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-3-hydroxyphenylcarbamoyl)ethyl]piperidin-4-yl ester was made. Using this ester, and following the procedure described in Example 2 and substituting the appropriate amine, the title compound was prepared. MS m/z [M+H+] calcd for C35H38N4O5, 595.7; found, 595.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].Cl.[CH:27](OCC)(OCC)[O:28][CH2:29][CH3:30]>>[C:19]([C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([N:1]=[CH:27][O:28][CH2:29][CH3:30])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: Cl
Product: CCOC=Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 50 °C

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (500 g) in triethyl orthoformate was treated with concentrated hydrochloric acid (10 ml) and heated at 50° C. After 8 hours the reaction mixture was evaporated to give a solid which was washed (heptane) and air-dried to give 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylthiopyrazole (217 g), m.p. 68° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-])=O)=[CH:40][CH:39]=2)=[N:4]1)[CH3:2].[OH-].[Na+]>C(O)(=O)C.[Zn]>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[CH:42][CH:43]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(-c2ccc(CN4CCCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (0.487 mmol) in glacial acetic acid (4 mL) was added zinc powder (3.41 mmol). After 1 h, the reaction was filtered and the zinc residue was rinsed with acetic acid. The filtrate was concentrated under reduced pressure and azeotroped five times with 1:1 methanol/toluene to remove residual acetic acid. The crude aniline was dissolved in methanol, treated with 6N NaOH (1.46 mmol) and heated to 70° C. After 5 h, the reaction mixture was concentrated under reduced pressure and the residue was suspended in cold water and stirred vigorously. The precipitate was collected by filtration and dried to constant weight under high vacuum to give title compound. ESMS [M+H]+: 463.4
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:7][C:5]([NH2:6])=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=1.Cl.[C:26](=N)(OC)[CH3:27].O>CO>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:8]1[C:2]([Cl:1])=[CH:3][C:4]2[N:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:26]([CH3:27])=[N:6][C:5]=2[CH:7]=1
Reactant: COC(C)=N
Reactant: Nc1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)c(Cl)cc2n1C1CCOCC1
Yield: 40.8 %

Procedure:
To a solution of 2-(4-chloro-2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 112-3) (0.04 g, 0.2 mmol) in methanol (1.2 mL) was added methyl acetimidate hydrochloride (0.06 g, 0.6 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.03 g, 79% yield) as a yellowish-brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]3[CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]3[CH2:20][CH2:19]3)(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cn1
Solvent: ClCCl
Product: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of 4-(6-amino-pyridin-3-yl)-N-cyclopropylbenzenesulfonamide (1.04 g, 3.59 mmol) in DCM (12 mL) was added portionwise N-bromosuccinimide (0.64 g, 3.59 mmol). The reaction was stirred for 1 h, then was filtered. The filtrate was washed with sat. aq. Na2S2O4 (20 mL), sat. aq. NaHCO3 (10 mL), then dried over Na2SO4 and concentrated to give 4-(6-amino-5-bromo-pyridin-3-yl)-N-cyclopropyl-benzenesulfonamide (1.07 g, 81% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.30 (d, J=2.01 Hz, 1H), 8.12 (d, J=2.01 Hz, 1H), 7.92 (d, J=8.53 Hz, 2H), 7.76 (d, J=8.53 Hz, 2H), 2.19 (tt, J=6.71, 3.58 Hz, 1H), 0.17-0.83 (m, 4H). MS (EI) m/z: 368, 370 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq. NH4OAc, 2 min gradient) tR=1.68 min, 90% integrated area.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][C:5]#[N:6].[CH3:9][NH:10][N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:5]([N:4]=[C:3]([N:10]([CH3:9])[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[S:2][CH3:1])#[N:6]
Reactant: CSC(=NC#N)SC
Reactant: CNN=Cc1ccccc1
Solvent: CC#N
Product: CSC(=NC#N)N(C)N=Cc1ccccc1

Procedure:
A mixture of cyanocarbonimidodithioic acid dimethyl ester (1.46 g) and benzaldehyde N-methyl hydrazone (1.34 g) in acetonitrile was heated under reflux for 50 hr. The reaction mixture was cooled to 25° to give the title compound as colourless crystals, m.p. 132°-133° (0.73 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]CCCCC.[Si](C=[N+]=[N-])(C)(C)C>CO.C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCCCCC
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a stirred solution of 4-hydroxy-3-nitrobenzoic acid (3.00 g, 0.0164 mol) in MeOH-benzene (1:4, v/v) was added dropwise 2.0 M-n-hexane solution of TMSCHN2 (8.2 mL, 0.0164 mol) at room temp. After the resulting solution was stirred for 4 hr at room temp, the mixture was evaporated off in vacuo. The oily residue was chromatographed on silica-gel with CHCl3 as eluent to afford 4.23 g (79%) methyl 4-hydroxy-3-nitrobenzoate as a pale yellow crystalline material.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])(O)=[O:8].[NH4+:18].[OH-].Cl>C(Cl)Cl.CN(C=O)C>[C:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])(=[O:8])[NH2:18]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(C=O)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
Oxalyl chloride (13.3 mL, 152 mmol) and DMF (50 μL) were added to suspension of 3-carboxybenzaldehyde (11.4 g, 76.2 mmol) in 200 mL CH2Cl2 and stirred at 23° C. for 18 h. The resulting clear solution was concentrated, dissolved in 100 mL CH2Cl2, and concentrated again. The crude acid chloride was dissolved in 20 mL THF, poured into a mixture of concentrated NH4OH (26 mL, 381 mmol) with 100 mL crushed ice, and allowed to warm to 23° C. with stirring. The mixture was acidified with conc. HCl to pH ˜3, then concentrated to remove THF. The resulting aqueous suspension was filtered and the white solid product dried under vacuum to give 7.4 g (65%) of 3-carbamoyl-benzaldehyde compound 1a: 1H NMR (DMSO-d6)δ 10.06 (1 H, s), 8.40 (1 H, s), 8.19 (1 H, s), 8.17 (1 H, d, J=6.6 Hz), 8.04 (1 H, d, J=7.7 Hz), 7.69 (1 H, t, J=7.7 Hz), 7.56 (1 H, s); IR (KBr pellet) 3391, 3205, 1711, 1694, 1664, 1385, 1217. Anal. (C8H7NO2•0.1H2O) C, H, N.
Reaction SMILES: C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC(C)([O-])C.[Na+].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[S:37][C:38]([CH2:40][CH2:41][CH3:42])=[N:39][C:32]=12.[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([S:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[C:48]([NH2:50])[CH:49]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([S:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[C:48]([NH:50][C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[S:37][C:38]([CH2:40][CH2:41][CH3:42])=[N:39][C:32]=23)[CH:49]=1
Reactant: CCCc1nc2c(Cl)ccnc2s1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Nc3cc(C)ccc3Sc3ccccc3)ccnc2s1
Temperature: 25 °C
Yield: 14.8 %

Procedure:
A dry nitrogen-purged flask was charged with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (38 mg, 0.111 mmol), tris(dibenzylideneacetone)-dipalladium (25.4 mg, 0.0277 mmol), and sodium tert-butoxide (82.4 mg, 0.8322 mmol). A solution of the product of Example 5G (118 mg, 0.5548 mmol) in anhydrous toluene (2 mL) and a solution of the product from Example 5I (107.5 mg, 0.4993 mmol) in toluene (3 mL) were added via syringe. The reaction was heated at reflux in a preheated 120° oil bath for 18 hours, cooled to room temperature, treated with additional tris(dibenzylideneacetone)dipalladium (25.4 mg), and heated at reflux for an additional 2.5 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. Purification by silica gel flash chromatography with a gradient of 1% to 3% ethyl acetate/methylene chloride afforded the title compound (29 mg, 0.074 mmol, 15%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.00 (t, J=7.35 Hz, 3H) 1.71-1.90 (m, 2H) 2.38 (s, 3H) 3.05 (t, J=7.35 Hz, 2H) 6.87 (d, J=5.52 Hz, 1H) 7.07 (dd, J=7.91, 1.29 Hz, 1H) 7.12-7.31 (m, 5H) 7.37-7.46 (m, 2H) 8.15 (d, J=5.52 Hz, 1H) 8.52 (s, 1H); MS (DCI/NH3) m/z 392 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[Na].[CH3:26][SH:27]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6]([S:27][CH3:26])[C:3]=1[C:4]#[N:5]
Reactant: CS
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCC[C@H]2C)n1
Agent: [Na]
Solvent: CN(C)C=O
Product: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 2,6-difluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile (162 mg, 0.492 mmol) in DMF (4 mL), was added methyl mercaptan sodium salt (ca. 15% in water, 319 mg, 0.683 mmol). The solution was stirred at room temperature overnight in a capped 10 mL vial. The mixture was poured onto water (15 mL). The formed solid was filtered, washed by water and dried to afford the title compound (86 mg) as a light yellow solid. LC-MS (ES) m/z=358 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C=O)[CH2:12][CH2:11]2)[CH:4]=[CH:5][N:6]=1>O1CCOCC1.Cl>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1CCCC1CCN(C=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nccn1CCCC1CCNCC1
Yield: 68.7 %

Procedure:
A mixture of 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde (3.8 g, 0.016 M) in dioxane (100 ml) and 2 N HCl (25 ml) was heated and refluxed for 51/2 hrs. After this period, solvent was removed, and 1 N NaOH (50 ml) was added to the residue. This mixture was then extracted with methylene chloride (5×50 ml). The combined extracts, dried over sodium sulfate, were stripped to dryness to yield 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]piperidine (2.3 g, 65% yield).