Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:19]2[CH:18]=[CH:17][CH:16]=[C:12]3[C:11]=2[C:10](=[O:20])[NH:14][C:13]3=[O:15])=[CH:4][N:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(Cc3ccc(Cl)nc3)cccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.7 %

Procedure:
2-chloro-5-chloromethylpyridine (5 g) was dissolved in dimethylformamide (60 ml) and to the solution was added phthalimide (6.29 g), followed by stirring at room temperature for 17 hours. The solvent of the reaction solution was removed under reduced pressure and the residue was extracted with water and dichloromethane to yield a white solid (6.2 g, 74%).
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.Cl[C:32](OC)=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([O:33][CH3:32])=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: COC(=O)Cl
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting methyl chloroformate and making non-critical variations provided the title compound as an oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]O)=[CH:5][CH:4]=1.[Na].C([OH:15])C>N>[OH:15][CH:9]([C:6]1[CH2:5][CH:4]=[C:3]([O:2][CH3:1])[CH2:8][CH:7]=1)[CH3:10]
Reactant: CCO
Reactant: COc1ccc(CCO)cc1
Agent: N
Agent: [Na]
Product: COC1=CCC(C(C)O)=CC1

Procedure:
A solution of 40 g of 2-(4-methoxyphenyl)ethanol in 80 ml of ethanol and 800 ml of ammonia reduced with 30.4 g of sodium to yield 27.4 g, bp 87°-89° (0.7 mm), identified by nmr.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1N1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-Chloro-3-nitropyridine (3.0 g, 18.92 mmol), 1,2,3,4-tetrahydroisoquinoline (2.37 ml, 18.92 mmol), and sodium carbonate (3.1 g, 28.62 mmol) were added to anhydrous N,N-dimethylformamide (30 ml). The reaction mixture was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water three times, and then washed with a saturated sodium chloride solution. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 4.8 g of the titled compound as yellow oil. (Yield: 98%).
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])[C@H:7]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])[NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11]C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([O:5][CH:6]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])[C@H:7]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:32])[NH2:33])[NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH2:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(C)C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
In 100 ml of methanol was dissolved 3.73 g of N-benzyloxycarbonyl-L-leucyl-L-argininal dibutyl acetal obtained. In nitrogen atmosphere, 1 g of palladium black was added to the solution and the mixture was subjected to catalytic hydrogenation at room temperature for 2 hours. After palladium black was removed by filtration, the filtrate was concentrated under reduced pressure to give 2.75 g of L-leucyl-L-argininal dibutyl acetal.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C(Cl)(Cl)Cl>[CH3:2][N:3]([OH:4])[C:21]([NH:20][C:15]1[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=1)=[O:22]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(O)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A mixture of 10 g of N-methyl-hydroxylamine hydrochloride in 100 ml of chloroform was stirred while 18 ml of triethylamine were added at 0° C. Then, 20 g of 3,5-dichlorophenyl isocyanate in 30 ml of chloroform were added to the mixture at 10° to 15° C and the mixture was stirred for 5 hours at 20° C and was then distilled to dryness under reduced pressure. The residue was taken up in water and dried to obtain 22 g of N-methyl-N-hydroxy-N'-(3,5-dichlorophenyl)-urea melting at 131°-132° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)cc2)CC1
Yield: 92.1 %

Procedure:
A solution of 1-methyl-4-(4-nitrophenyl)piperazine (1.03 g, 4.66 mmol) in MeOH (100 ml) was hydrogenated at 20° C. at atmospheric pressure using an H-Cube (flow rate at 1 ml/min and full hydrogen mode) using a Pd/C cartridge. The solvent was removed in vacuo to afford 4-(4-methylpiperazin-1-yl)benzenamine (0.82 g, 4.29 mmol, 92%) as an off-white solid. 1H NMR (CDCl3) 2.37 (3H, s), 2.62 (4H, t), 3.09 (4H, t), 3.40 (2H, br. s), 6.65 (2H, d), 6.82 (2H, d). LCMS (1) Rt: 0.98 min; m/z (ES+) 192.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12](OC)=[O:13])=[C:5]([F:16])[CH:4]=1)#[N:2].[BH4-].[Li+]>C1COCC1.[Cl-].[NH4+]>[F:16][C:5]1[C:6]([CH2:11][CH2:12][OH:13])=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: COC(=O)Cc1cc(OC)c(C#N)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCO)c(F)cc1C#N
Reaction time: 12 h

Procedure:
To a solution of methyl (4-Cyano-2-fluoro-5-methoxyphenyl)acetate (5.0 g, 22 mmol) in THF (50 mL) at 0° C. was added lithium borohydride (14.6 mL, 29.1 mmol). The reaction was stirred for 12 h, then was diluted with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. Silica gel column chromatography (50->100% EtOAc:hex.) provided 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H NMR (500 MHz, CD3OD) δ 7.19 (d, J=5.3 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H), 4.21 (br s, 1H), 3.88 (s, 3H), 3.82 (m, 2H), 2.92 (m, 2H); LC/MS: [(M+1)]+=196.2; tR=0.58 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[CH:22][CH:21]=1)=[O:12])[CH3:9].B([C:37]1[CH:42]=[CH:41][C:40]([C:43]2([C:46]([OH:48])=[O:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[CH:22][C:23]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3([C:46]([OH:48])=[O:47])[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)=[CH:24][CH:25]=1)=[O:12])[CH3:9]
Reactant: CC(OC(=O)Nc1ccncc1-c1ccc(OS(=O)(=O)C(F)(F)F)cc1)c1ccccc1Cl
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Product: CC(OC(=O)Nc1ccncc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: trifluoro-methanesulfonic acid 4-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-pyridin-3-yl}-phenyl ester and 1-(4-boronophenyl)cyclopropanecarboxylic acid. After workup the crude material was purified via preparatory HPLC to give the title compound.
Reaction SMILES: ClC1C=CC(C2NC(C3C=C[C:16]([O:19]C)=[CH:15]C=3OCC)=NC2CC(C)C)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47][CH2:46][N:45](C)[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65]CC[CH2:62]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:43][CH2:44][N:45]([C:16](=[O:19])[CH3:15])[CH2:46][CH2:47]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]([CH3:62])[CH3:65])=[CH:31][CH:30]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
1-{4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-1H-imidazole (Example 10) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 541.2580, calculated for C26H32N4O4Cl [(M+H)+]541.2576.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.O=[C:18]([CH3:31])[CH2:19][C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C.C(OCC)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:31])[C:19]([C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)O[C@H](C)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Solvent: CCOCC
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)(phenyl)methanone (1.16 g, 5.0 mmol) in ethanol (20 ml) was added (R)-1-phenylethyl 3-oxobutanoate (1.3 g, 6.5 mmol) followed by ytterbium triflate (294 mg, 0.5 mmol). The mixture was stirred at room temperature for 12 hours, then the ethanol was removed under reduced pressure, and the residual viscous oil dissolved in ethyl acetate. The organic phase was poured into a separatory funnel and washed with 1M aqueous hydrochloric acid, water, then brine. The organic phase was seoarated, and the solvent was removed under reduced pressure to provide a viscous oil. This was dissolved in a small amount of diethyl ether, and the solution allowed to stand at room temperature overnight. The white precipitate formed was filtered, washed with cold diethyl ether, and dried under reduced pressure, to provide (R)-1-phenylethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate (1.33 g, 67%) as a white powder. Rf=0.26 using 80:20 hexanes:ethyl acetate eluent on glass backed silica gel plates. 1H NMR (CDCl3, 400 MHz) δ 8.98 (d, 1H, J=8.9 Hz); 7.96 (d, 1H, J=7.4 Hz); 7.72 (d, 1H, J=1.95 Hz); 7.6-7.1 (m, 10H); 5.88 (q, 1H, J=6.6 Hz); 3.05 (s, 3H); 1.3 (d, 3H, J=6.6 Hz). LC MS (CI) shows M+H 402.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:15]2[NH:16][C:17](=[O:32])[C:18]3[C:19](=[C:21]([CH2:30][CH3:31])[N:22]([CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:23]=3)[N:20]=2)[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:8][CH:9]=1)(=[O:3])[CH3:2].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([C:15]2[NH:16][C:17](=[O:32])[C:18]3[C:19](=[C:21]([CH2:30][CH3:31])[N:22]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:35])[CH2:26][CH2:25]4)[N:23]=3)[N:20]=2)[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCNCC3)nc2c(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCN(C)CC3)nc2c(=O)[nH]1
Reaction time: 14 h
Yield: 39.4 %

Procedure:
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(4-piperidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 49) (100 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL) and formaldehyde (27 mg, 0.01 mL of a 37-41% solution) was added. After 30 min stirring sodium triacetoxyborohydride (108 mg, 0.51 mmol) was added and stirring continued for 14 h. Further formaldehyde (0.01 mL of 37-41% solution) and sodium triacetoxyborohydride (108 mg, 0.51 mmol) were added and stirring continued for a further 4.5 h. Starting material still remained so further formaldehyde (0.01 mL of 37-41% solution) and sodium triacetoxyborohydride (108 mg, 0.51 mmol) were added and stirring continued for a further 18 h. The reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution then brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (elution with 94:6:0.6 dichloromethane/methanol/0.88 ammonia) gave the product (41 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:18][C:8]1[C:7](=[O:19])[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncc2cc(CBr)c(=O)n(C3CCCC3)c2n1
Reaction time: 3 h
Yield: 32 %

Procedure:
8-Cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.5 g, 12.7 mmol) and N-bromosuccinimide (2.6 g, 14.6 mmol) in carbon tetrachloride (100 ml) were irradiated with ultraviolet light allowing the temperature to reach 45° C. over 3 hours. The mixture was filtered, washed with dilute sodium sulfite solution, then brine, and dried over anhydrous magnesium sulfate. The crude product was chromatographed on silica gel eluting with 1:1 ethyl acetate:hexane to provide 6-bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a crystalline solid yielding (1.46 g, 32% yield), mp 103-105° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][CH:11]([CH3:14])[CH2:12][OH:13].[H-].[Na+].O>C1COCC1>[Br:1][C:2]1[C:3]([O:13][CH2:12][CH:11]([CH3:14])[CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COc1nc(Cl)ncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of 5-bromo-2,4-dichloropyrimidine (2.56 mL) and 2-methyl-1-propanol (1.85 mL) in THF (80 mL) was added 60% sodium hydride (960 mg) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give a crude product of the title compound (4.15 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH:37]=[CH2:38]>C(#N)C.O>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[N:27]([CH2:38][CH:37]=[CH2:36])[CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: C=CCBr
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C=CCN1C2CCC1CC(=C1c3ccccc3Oc3cc(C(=O)N(CC)CC)ccc31)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.3 %

Procedure:
To a sample of compound 10a (0.37 g, 0.95 mmol) in 6 mL acetonitrile was added potassium carbonate (0.53 g, 3.81 mmol) and allyl bromide (80 μL, 0.95 mmol). The mixture was stirred at room temperature for 20 h. The reaction was diluted with water and extracted with CH2Cl2. The combined organic extracts were dried over magnesium sulfate and concentrated. The product was purified by flash column chromatography on silica gel, eluting with 10% 0.5 M NH3 in methanol/CH2Cl2 to yield 0.11 g (0.25 mmol) of Compound 14a. The product was converted into its HCl salt using ethereal hydrogen chloride. MS m/z=429.0 (M+1); 1H NMR 300 MHz (CDCl3) δ 1.1-1.4 (m, 6H), 1.7 (m, 2H), 2.3 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.6 (m, 4H), 4.0 (m, 2H), 4.4 (m, 2H), 4.7 (m, 2H), 5.5-5.9 (m, 4H), 6.3 (m, 2H), 7.1-7.4 (m, 7H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:10][C:11]1[C:12]([O:35][CH3:36])=[C:13]([C:17](=[O:34])[CH2:18][CH2:19][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)=[O:21])[S:14][C:15]=1[CH3:16])[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([O:10][C:11]1[C:12]([O:35][CH3:36])=[C:13]([CH:17]([OH:34])[CH2:18][CH2:19][CH:20]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)[OH:21])[S:14][C:15]=1[CH3:16])[CH:8]=[CH2:9]
Reactant: C=CCOc1c(C)sc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1c(C)sc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (100 mg) was added to a solution of 1-(4-allyloxy-3-methoxy-5-methyl-thiophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione (1.0 g, 2.2 mmol) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred at room temperature for 0.5 hour and quenched with 2 N sodium hydroxide. The cake was filtered and washed with THF-Et2O (1:1, v/v). The combined filtrates were evaporated to give 1-(4-allyloxy-3-methoxy-5-methylthiophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4- butanediol, which was used directly in the next experiment without further purification. The title compound had n.m.r. (CDCl3): δ 0.88 (b, CH2CH2), 2.43 (s, SCH3), 3.85, 3.86, 3.87 (3s, 4 OCH3), 4.54 (d, CH2CH=CH2), 4.72 (b, 2 CHOH), 5.22-5.45 (CH2CH=CH2), 6.16 (m, CH2CH-CH2), 6.60, 6.74 (2s, ArH).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)[N:17]=2)=[CH:9][CH:8]=[C:7]([F:26])[C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:17]=2)=[CH:9][CH:8]=[C:7]([F:26])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(-c2csc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(O)cc3)cs2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
A solution of 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide (0.20 g, 0.53 mmol) in 15 ml of DCM was cooled to −78° C. followed by addition of BBr3 (0.2 ml, 2.14 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated, the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as light yellow solid (0.06 g, 31%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 2H), 6.83 (d, J=8.40 Hz, 2H), 7.13 (m, 1H), 7.40 (m, 1H), 7.78 (d, J=8.80 Hz, 2H), 7.88 (br s, 1H), 7.91 (s, 1H), 8.17 (br s, 1H) and 9.64 (br s, 1H). MS ES+ (363.25), HPLC (method I) Rt=14.57 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])=[CH:5][CH:4]=1.[N:25]([CH2:28][CH3:29])=[C:26]=[O:27]>CN(C=O)C>[CH3:24][C:19]1[C:18]([C:10]2[N:11]([C:26]([NH:25][CH2:28][CH3:29])=[O:27])[C:12]3[C:17]([C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: CCN=C=O
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)n1c(-c2c(C)noc2C)c(-c2ccc(OC)cc2)c2ccccc21
Temperature: 70 °C

Procedure:
4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (15 mg, 0.06 mmol) and isocyanatoethane (40 μl) were mixed 1 ml dry DMF under nitrogen. The mixture was heated at 70° C. for 3 h. 100 μl isocyanatoethane were added and the heating at 70° C. continued over night. The crude reaction mixture was purified by prep HPLC. 8.0 mg 2-(3,5-dimethylisoxazol-4-yl)-N-ethyl-3-(4-methoxyphenyl)-1H-indole-1-carboxamide was obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[Cl:10]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1n[nH]c2ncccc12
Temperature: 45 °C

Procedure:
1H-pyrazolo[3,4-b]pyridine (89 Mg) and N-chlorosuccinimide (220 Mg) were combined in CH2Cl2 (4 mL) and heated at 45° C. for 16 hr, then cooled to room temperature. The resultant mixture was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to afford 3-chloro-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:23]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([NH:36][C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([N:24]4[CH2:25][CH2:26][CH:22]([N:21]([CH3:37])[CH3:20])[CH2:23]4)[S:28][C:29]=3[CH:35]=2)=[O:9])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4ccc(F)c(F)c4)cc3s2)C1
Yield: 77 %

Procedure:
Prepare according to Method C (Example 9), using 3,4-difluorocinnamic acid (107 mg, 0.581 mmol), oxalyl chloride (250 μL, 2.87 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (100 mg, 0.382 mmol) to afford the title compound (126 mg, 77%). mass spectrum (m/e): 429.0 [M+H], 427.0 [M−H]. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.25 (d, 1H, J=0.9 Hz), 7.72 (m, 1H), 7.55 (d, 1H, J=15.3 Hz), 7.52-7.48 (m, 2H), 7.43-7.41 (m, 2H), 6.80 (d, 1H, J=15.8 Hz), 3.70 (dd, 1H, J=9.7, 7.0 Hz), 3.61 (m, 1H), 3.47 (m, 1H), 3.26 (dd, 1H, J=9.9, 8.1 Hz), 2.88 (m, 1H), 2.21-2.17 (m, 7H), 1.90 (m, 1H).