Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C(CCO)=CC=CC=1.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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:39]2[CH:40]=[CH:41][S:37][CH:38]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)C(O)(c1cccc(-c2ccsc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 86.5 %

Procedure:
To a suspension of 1-(3-bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.70 g), 3-thiopheneboronic acid (607 mg) and 2M aqueous sodium carbonate solution (3.16 ml) in toluene-ethanol (6:1) (17.5 ml) was added tetrakis(triphenylphosphine)palladium(0) (110 mg), and the mixture was heated under reflux for 3 h under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chomatography (eluent, hexane:ethyl acetate=6:1→4:1→3:1). Recrystallization from ethyl acetate-hexane gave the title compound (1.48 g) as colorless powder crystals.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(=S)=S>O>[CH2:6]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[C:17]=1[C:22]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:31])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(Cc2cc3ccccc3o2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Solvent: O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)cc1
Yield: 84.2 %

Procedure:
Tin tetrachloride (6.5 mL, 55.5 mmol) was added dropwise over a 30 minute period to a stirred solution of 2-benzyl-benzofuran (10.0 g, 48.01 mmol), anisoyl chloride (8.51 g, 49.93 mmol) and carbon disulfide (53 mL) at room temperature under a dry nitrogen atmosphere. After 15 h the reaction mixture was added to water and extracted with dichloromethane. Silica gel was added to the dichloromethane phase and the solvent was removed. The adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate as eluent) to provide the title compond as a white solid (13.84 g, 84%): mp 84-85° C.: NMR (CDCl3); δ7.87 (dm, J=9 Hz, 2 H), 7.46 (dm, 1 H), 7.36-7.12 (m, 8 H), 6.97 (dm, J=9 Hz, 2 H), 4.29 (s, 2 H), 3.90 (s, 3 H): MS (EI):
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][C:32](Cl)=[O:33]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:32]([O:31][CH3:30])=[O:33])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC)C3)cc1

Procedure:
Method as example 34 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2 yl)phenyl)urea (example 13) and methylchloroformate as starting materials.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[N:10][C:9]([C:17]([O:19]C)=[O:18])=[CH:8]2>O.O.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[N:10][C:9]([C:17]([OH:19])=[O:18])=[CH:8]2
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cnc(C(=O)O)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium hydroxide (4.38 g, 109.4 mmol) in 70 ml of water was added to a solution of 6,7-dimethoxy-3-isoquinolinecarboxylic acid, methyl ester (22.54 g, 91.2 mmol) in 1800 ml of water:tetrahydrofuran 1:1. After stirring overnight at room temperature, the tetrahydrofuran was distilled off in vacuo and the pH of the remaining aqueous solution was brought to 3 with 3N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and dried in vacuo. Yield: 19.57 g; melting point 228.2° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[N:1]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[N+:2]=[N-:3]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1CN=[N+]=[N-]
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL of DMF at room temperature. After stirring overnight, reaction mixture was quenched with 25 mL of water. The aqueous was extracted with ethyl acetate (3×30 mL) and the combined organics were washed with water (2×40 mL) and 50 mL of brine. The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield methyl 2-(azidomethyl)-5-chlorobenzoate (429 mg, 97%) as an off-white solid, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19](O)=[O:20])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:18][N:15]1[C:14]([C:19](=[O:20])[NH:36][CH:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2c(NC(=O)c3nc(C4CC4)cnc3Nc3cncnc3)cnn2C)CC1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 66 μmol; example 236, step 3) and 1-methyl-piperidin-4-ylamine (10 mg, 85 pimp according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (17 mg, 50%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([O:25]CC2C=CC=CC=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Solvent: CCO
Product: O=c1[nH]ccc2cc(OC3CCNCC3)ccc12
Temperature: 25 °C

Procedure:
Coumpound (11) was dissolved in ethanol/2 N HCl (1:1) and stirred at room temperature until complete conversion was achieved. The solvent was removed i. vac. and the residue was purified by preparative HPLC. The resulting trifluoroacetate was dissolved in 2 N HCl and lyophilized. After another lyophilization from water, 850 mg of the title compound could be obtained as HCl salt. Rt=0.75 min (Method B). Detected mass: 245.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][N:19]([CH3:21])[CH:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccccc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]2[NH:28][N:29]=[N:30][C:26]=2[CH:25]=1>C(OCCO)C>[N:28]1[C:27]2[CH:31]=[CH:32][C:24]([NH:23][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:25][C:26]=2[NH:30][N:29]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc2ncc(C#N)c(Nc3ccc4nn[nH]c4c3)c2c1
Yield: 95.8 %

Procedure:
Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 161.0 mg (1.2 mmol) of 5-aminobenzotriazole to give 302.9 mg (95.8%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 316.9. HRCIMS calcd: 316.107 for C17H12N6O(M+), obsd 316.1081
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.[N:24]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([NH:31][C:21]([C:10]2[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=2)=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Br)cc2)C1
Reactant: NN1CCCCCC1
Product: O=C(NN1CCCCCC1)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Br)cc2)C1

Procedure:
This compound was obtained following the same method described in Example 1 starting from 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride and azepan-1-amine.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OO)=[O:22]>>[O:22]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=COO
Product: CCCCCCCCC1OC1CCCCCCCC(=O)O

Procedure:
9,10-Epoxyoctadecanoic acid is prepared according to a method described in “Salimon et al., (2009), European Journal of Scientific Research, 32(2), 216-222” and in which 71 mmol of oleic acid are treated with freshly prepared performic acid at ambient temperature for 3 hours with magnetic stirring (400 rpm). A white powder of 9,10-epoxyoctadecanoic acid (51 mmol) is obtained, with a degree of purity of 65% and a yield of 72%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C)C=O.O1CCCC1>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:22][C:19]1[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1
Temperature: 110 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
4-Chloro-8-nitroquinoline (176 mg, 0.85 mmol) and 4-aminophenol (93 mg, 0.85 mmol) were dissolved in dimethylformamide, and to which 1.0 M potassium tert-butoxide (0.95 mL) in tetrahydrofuran was slowly added dropwise at room temperature, which was then heated and stirred at 110° C. for seven hours. When the reaction was completed, the resultant was extracted with ethyl acetate and aqueous sodium chloride, and the combined organic layers were dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=½) to obtain 140.6 mg of the desired compound as a reddish brown solid (yield 59.0%).
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:8][C:9](=[O:23])[CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].O>CN(C=O)C>[C:24]1([CH:7]([NH:8][C:9]([CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])=[O:23])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CN1C(=O)COc2c(O)cccc21)NC(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1OCC(=O)N2CC(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
N-diphenylmethyl-2-(8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamide (735 mg) was dissolved in DMF (30 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (785 mg) and methyl bromoacetate (0.35 ml) were added to the solution, and the mixture was stirred at room temperature for 18 hours. Water (25 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated. The resultant residue was recrystallized from ethyl acetate/n-hexane to obtain the object compound (492 mg, yield 56%)
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH3:6][N:7]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:38]=[CH:39][C:40]=2[CH3:41])[O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH:25]=[C:26]([NH:28][C:29]([CH:31]4[CH2:33][CH:32]4[C:34](OC)=[O:35])=[O:30])[N:27]=3)[N:24]=2)=[O:13])=[CH:10][C:9]([CH3:42])=[N:8]1.[Cl-].[NH4+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[OH:35][CH2:34][CH:32]1[CH2:33][CH:31]1[C:29]([NH:28][C:26]1[N:27]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:15]([NH:14][C:12]([C:11]4[N:7]([CH3:6])[N:8]=[C:9]([CH3:42])[CH:10]=4)=[O:13])[CH:16]=3)=[N:24][N:23]2[CH:25]=1)=[O:30]
Reactant: COC(=O)C1CC1C(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5CO)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a suspension of calcium chloride (135 mg, 1.1 mmol) in tetrahydrofuran/ethanol (2/1, 1 mL) was added a solution of sodium borohydride (92 mg, 2.2 mmol) and methyl 2-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropanecarboxylate (180 mg, 0.37 mmol) in tetrahydrofuran/ethanol (2/1, 1 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0, and then methanol/ethyl acetate=0/100→5/95) to give the title compound (35 mg, 20%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=1)[CH3:2].[C:17]([C:19]1[O:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1)#[N:18].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:24]([C:22]2[O:23][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[O:25])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)c(N2CCCCC2)c1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 54 %

Procedure:
Using a procedure similar to Example 3, step (d), 4-ethoxy-2-piperidin-1-yl-phenylamine (64 mg, 0.29 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (66.6 mg, 0.430 mmol) in the presence of DIEA (111 μL, 0.63 mmol) to afford 53 mg (54%) of the title compound as a light yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 9.49 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.25 (d, 1H, J=2.7 Hz), 7.22 (d, 1H, J=2.8 Hz), 6.77 (d, 1H, J=2.8 Hz), 6.67 (dd, 1H, J=2.8, 8.9 Hz), 2.82 (m, 4H), 4.02 (q, 2H, J=7.0 Hz), 2.82 (m, 4H), 1.80-1.82 (m, 4H), 1.64 (br s, 2H), 1.41 (t, 3H, J=7.0 Hz); Mass spectrum (ESI, m/z): Calcd. for C19H21N3O3, 340.1 (M+H), found 340.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]([CH2:11][NH2:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:19][N:16]1[CH2:15][CH2:14][N:13]([C:3]2[C:4]([CH2:11][N:12]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:18][CH2:17]1
Reactant: BrCCCCBr
Reactant: Cc1cc([N+](=O)[O-])cc(CN)c1N1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(CN2CCCC2)c1N1CCN(C)CC1
Yield: 53 %

Procedure:
A mixture of [3-methyl-2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanamine (188 mg, 0.71 mmol), 1,4-dibromobutane (93 μL, 1.1 eq) and K2CO3 (490 mg, 5 eq) in 15 mL of acetonitrile was refluxed for 48 h. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow oil (120 mg, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:10]3(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:6]=2[CH:24]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=3)[C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2csc3ccc(Cl)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2scc(C3=CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
To a solution of 0.32 gm (0.86 mMol) 5-chloro-3-(4-hydroxy-1-(tert-butoxycarbonyl)piperidin-4-yl)benzothiophene in 3.0 mL dichloromethane were added 2.0 mL trifluoroacetic acid. The reaction mixture was stirred for 4 hours at room temperature and was then concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with chloroform containing 5% methanol. Fractions shown to contain product were combined and then concentrated under reduced pressure to give 0.14 gm (64%) of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzothiophene as a foam. This material was dissolved in diethyl ether and the solution was saturated with hydrogen chloride. The resulting solution was concentrated under reduced pressure to give the title compound as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O)#[N:25].O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:29]([C:28]1[CH:27]=[C:26]([CH:34]=[CH:33][CH:32]=1)[C:24]#[N:25])[O:14]2
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1cccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 6.7 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (61 mg, 0.257 mmol) and K2CO3 (178 mg, 1.29 mmol) in acetone (3 mL) was added 3-cyanobenzoyl chloride (43 mg, 0.257 mmol). The reaction vessel was sealed and heated to 60° C. for 2 d. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 6 mg (7%) of 3-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile. Rf=0.33 (50% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17](OC)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:23][C:24]4[S:25][CH:26]=[C:27]([CH3:29])[N:28]=4)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)C2=C(O)c3sc4cc(Cl)ccc4c3S(=O)(=O)N2C)n1
Yield: 36 %

Procedure:
Prepared analogous to Example 1 from methyl 7-chloro-4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 36% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (70 mg, 0.10 mmol), copper (I) iodide (38 mg, 0.20 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) to a solution of 2-fluoro-5-iodobenzoic acid (0.53 g, 2.0 mmol) in triethylamine (4.2 mL, 30.0 mmol) and stir at room temperature for 1 h. Heat at 50° C. for 18 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 100:0 to 60:40 ethyl acetate:methanol. Triturate the resulting solid with 3:1 hexanes:methanol to give the title compound as an off-white solid (295 mg, 54%).