Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C:7]2[N:12]3[CH:13]=[C:14]([C:16]4[C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[NH:18][CH:17]=4)[CH:15]=[C:11]3[C:10](=[O:25])[N:9](CC3C=CC(OC)=CC=3OC)[CH:8]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:12]3[CH:13]=[C:14]([C:16]4[C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[NH:18][CH:17]=4)[CH:15]=[C:11]3[C:10](=[O:25])[NH:9][CH:8]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(Cn2cc(Cc3ccc(N)cc3)n3cc(-c4c[nH]c5ncccc45)cc3c2=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Nc1ccc(Cc2c[nH]c(=O)c3cc(-c4c[nH]c5ncccc45)cn23)cc1
Temperature: 120 °C

Procedure:
To a solution of EXAMPLE 23J (300 mg, 0.594 mmol) in CH2Cl2 (5 ml) was added trifluoroacetic acid (10 mL), and the mixture was heated at 120° C. in a microwave reactor (Biotage, Initiator) for 40 minutes. After cooling, the reaction mixture was diluted with toluene (50 mL) and concentrated. The residue was purified flash chromatography (CH2Cl2/tetrahydrofuran/CH3OH/Et3N, 50/50/1/1) to afford the title compound. LC-MS (ESI): m/z 356 (M+H), RT: 1.30 min; 1H NMR (400 MHz, dimethylsulfoxide, d6): δ 3.92 (s, 2H), 4.97 (s, 2H), 6.28 (d, J=5.6 Hz, 1H), 6.54 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.13 (dd, J=4.8, 3.2 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 8.18 (dd, J=6.8, 1.2 Hz, 1H), 8.27 (dd, J=3.6, 1.2 Hz, 1H), 10.46 (d, J=6.0 Hz, 1H), 11.74 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][C@@H:16]([CH3:18])[NH:15][CH2:14][C@@H:13]1[CH3:19].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([Cl:27])=[O:26]>C1C=CC=CC=1>[ClH:27].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][C@@H:16]([CH3:18])[N:15]([C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[CH2:14][C@@H:13]1[CH3:19]
Reactant: O=C(Cl)c1ccco1
Reactant: COc1ccccc1CCCN1C[C@@H](C)NC[C@@H]1C
Solvent: c1ccccc1
Product: COc1ccccc1CCCN1C[C@@H](C)N(C(=O)c2ccco2)C[C@@H]1C
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of trans-1-[3-(o-methoxyphenyl)propyl]-2,5-dimethylpiperazine [b.p. 146° - 150°C (2 mmHg), dipicrate, m.p. 260° - 265°C], 2-furoyl chloride and benzene.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C([BH3-])#N.[Na+].C(OC)(OC)OC.[CH:40](=O)[CH2:41][CH3:42]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH2:40][CH2:41][CH3:42])[CH2:27][CH2:28]2)=[O:22])=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCC=O
Reactant: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (48.8 mg) obtained in Example 32-2 was dissolved in anhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride (16.2 mg), trimethyl orthoformate (21.1 μl), propionaldehyde (13.9 μl), followed by stirring overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. A saturated aqueous sodium bicarbonate solution was added to the solution, followed by stirring. The resultant solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution, and then the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (33.2 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1[CH:32]=[CH:33][C:34](S(O)(=O)=O)=[CH:35][CH:36]=1.O.[CH2:42]([OH:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH:9]([O:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:10][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CC(C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 200.5 %

Procedure:
To a suspension of 3-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-oxo-butyric acid tert-butyl ester (1.24 g, 3.14 mmol) in Dichloromethane (10 mL) at room temperature was added 0.20 equiv TsOH.H2O (0.12 g, 0.63 mmol) and followed by dropwise 5.0 equiv of Benzyl alcohol (1.62 mL, 15.68 mmol). After stirring room temperature for 18 hrs, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain a crude title compound. The residue was purified by flask column chromatography on silica gel eluting with EtOAc/Hexane (10–40%) to give the title compound (0.75 g, 40%) as clear oil. TLC (40% EtOAc/Hexane) Rf=0.68; 1HNMR (CDCl3) δ 7.76 (d, J=7.2 Hz, 2H), 7.59 (d, J=7.5 Hz, 2H), 7.39 (t, J=7.5 Hz, 21H), 7.35–7.27 (m, 12H), 5.37 (d, J=9.6 Hz, 1H), 4.73–4.52 (m, 5H), 4.35 (d, J=6.6 Hz, 2H), 4.24–4.16 (q, J=6.6 Hz, 2H), 2.55–2.50 (m, 2H), 1.39 (s, 9H). MS(ES) for C37H39NO9 (MW=593.71): positive 611 (M+NH4+).
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(Cl)Cl.Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 2 h

Procedure:
38 g of ethoxy acrylate from Example 1 are initially introduced into 150 ml of methylene chloride. An aqueous solution of 15.4 g of ethyl 3-aminopropionate hydrochloride is added to this. A solution of 8.4 g of NaHCO3 in water is added dropwise to the two-phase system with vigorous stirring. After completion of the dropwise addition, the mixture is stirred for a further 2 hours, and the phases are subsequently separated. The organic phase is washed with water, dried over Na2SO4, and concentrated. The solid residue is slurried in diethyl ether and subsequently isolated. Yield: 38 g, melting point 107°-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=3)=[CH:22][C:13]=12.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)=[CH:22][C:13]=12
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3sc(-c4ccc(C=O)cc4)cc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3sc(-c4ccc(CN5CCOCC5)cc4)cc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
A suspension of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.24 mmol) in 1 mL of N,N-dimethylformamide and 4 mL of dichloromethane is prepared. To the mixture is added morpholine (0.03 mL, 0.32 mmol). The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (0.26 g, 1.2 mmol) is added. After stirring at 0° C. for 30 minutes a drop of acetic acid is added and the mixture is stirred at 0° C. for an additional 4 hours. Additional morpholine (0.01 mL, 0.1 mmol) and sodium triacetoxyborohydride are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The resultant light brown solution is partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride and water, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is triturated with acetone and water to provide 86 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(morpholin-4-ylmethyl)phenyl]thieno[2,3-b]pyridine-5-carbonitrile as a white solid, mp 106-108° C.; 1H NMR (DMSO-d6) δ 2.38 (br s, 4H), 3.51 (br s, 2H), 3.59 (br s, 4H), 3.86 (s, 3H), 7.40 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.77 (s, 1H), 8.19 (s, 1H), 8.42 (s, 1H), 9.80 (s, 1H); MS 525.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:7][CH2:6][C@@H:5]([CH3:29])[N:4]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:3]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:15][CH:14]([CH3:16])[CH2:13][C@H:12]([NH:17][C:18]([C:20]1[O:28][C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:19])[C:10](=[O:11])[NH:9][C@H:8]1[CH2:7][CH2:6][C@@H:5]([CH3:29])[N:4]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:3][C:2]1=[O:1]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ncccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C[C@H](NC(=O)c1cc2ncccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
Sulfur trioxide-pyridine complex (0.050 g, 0.31 mmol) was added to a solution of Furo[3,2-b]pyridine-2-carboxylic acid {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide (0.056 g, 0.103 mmol) in DMSO (1.0 ml) and triethylamine (0.085 ml, 0.6 mmol) was stirred at RT for 1 h. The reaction was incomplete; therefore, additional triethyl amine (0.04 ml, 0.3 mmol) and sulfur trioxide-pyridine complex (0.0.025 g, 0.15 mmol) was added ant the reaction was stirred an additional hour. The reaction mixture was diluted with water, then was extracted with EtOAc. Then, the organic layer was was extracted with brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (50% to 80% ethyl acetate/hexanes) gave the title compound (12.5 mg, 22%): 1H NMR: 1H NMR: 8.72 (1H, d), 8.66 (1H, d), 8.02 (1H, d), 7.93 (1H, dd), 7.85 (1H, d), 7.53 (1H, dd), 7.40 (1H, dd), 7.25 (d, 1H), 6.95 (1H, d), 5.15 (m, 1H), 4.77 (m, 2H), 3.72 (q, 1H), 2.20–2.08 (m, 2H), 1.78–1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec: M+H+=542.2.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[O:20])[C:16]([OH:36])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([O:36][C:16]2[C:17]([C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[S:30]([N:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[O:20])=[N:18][C:9]([Br:8])=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c(C(=O)NCc3ccc(F)cc3S(=O)(=O)N(C)C)nc(Br)c3cccnc23)cc1
Reaction time: 5 h

Procedure:
Triethylamine (0.65 mL, 4.66 mmol) was added slowly to a suspension of 5-bromo-N-{2-[(dimethylamino)sulfonyl]-4-fluorobenzyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide (1.50 g, 3.10 mmol) in chloroform (15 mL) to give a yellow cloudy solution. p-Toluenesulfonyl chloride (0.71 g, 3.73 mmol) was then added slowly and the mixture was aged at 40° C. for five hours. The mixture was quenched with 10% KHSO4 solution and the layers were separated. The aqueous layer was extracted twice more with CHCl3. The combined organic extracts were washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a crude yellow oil. The oil was dissolved in a minimal amount of CHCl3 and purified on an Isco column (110 g silica) running a 0 to 2.5% MeOH/CHCl3 gradient over 30 minutes. The collected fractions were concentrated in vacuo to afford the desired material as a white solid foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]([CH3:16])[NH:12][NH:11][N:10]=1
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1NNN=C1c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.8 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) was stirred at room temperature for 16 hrs, then concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to provide 350 mg (Yield 33%) of the title compound as white crystals. 1H NMR (500 MHz, CDCl3) δ ppm: 4.00 (3H, s) 7.18-7.25 (2H, m) 7.72 (1H, dd, J=8.4, 5.0 Hz); 13C NMR (126 MHz, CDCl3) δ ppm: 34.59, 117.73, 119.58, 120.43, 127.57, 135.11, 153.43, 161.69. LC/MS m/z 257/259.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1.Cl.[CH3:33][O:34][C:35](=[O:39])[CH2:36][NH:37][CH3:38].C(N(CC)CC)C>C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[O:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[N:3]=[C:2]([N:37]([CH3:38])[CH2:36][C:35]([O:34][CH3:33])=[O:39])[C:7]([C:8]#[N:9])=[C:6]([CH:10]4[CH2:15][CH2:14][CH2:13][O:12][CH2:11]4)[C:5]=3[C:16]#[N:17])[N:21]=2)=[CH:26][CH:27]=1
Reactant: CNCC(=O)OC
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCOC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)c1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(C2CCCOC2)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
239 mg (0.42 mmol) of the compound from Example 43A are dissolved in 6 ml of dry THF, and 116 mg (0.83 mmol) of sarcosine methyl ester hydrochloride and 126 mg (1.25 mmol) of triethylamine are then added in succession. The reaction mixture is stirred at RT for 10 h. The solvent is then removed on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[S:19][C:20]([C:23]#[N:24])=[CH:21][N:22]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:18]3[S:19][C:20]([C:23]#[N:24])=[CH:21][N:22]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cc(N)ncn2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1
Reaction time: 0.5 h

Procedure:
6-(4-Methyl-piperazin-1-yl)-pyrimidin-4-ylamine (97 mg, 0.50 mmol) was stirred in 2 mL anhydrous THF under N2. Sodium hydride (43 mg, 60% dispersion, 1.10 mmol) was added and after stirring for 30 minutes, 2-chloro-thiazole-5-carbonitrile (87 mg, 0.60 mmol). After LCMS indicated complete conversion, the reaction was quenched with MeOH, neutralized with 10% citric acid (aq). The resulting precipitate was filtered, washed with water and after air drying was washed with hexane. 1H-NMR (400 MHz, DMSO) 12.00 (1H, s), 8.42 (1H, s), 8.25 (1H, s), 6.21 (1H, s), 3.54 (m, 4H), 2.39 (m, 4H), 2.21 (s, 3H). M+1=302.3.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.I[CH3:22].CO>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N:14]([CH3:22])[C:15]1[CH:20]=[N:19][CH:18]=[N:17][CH:16]=1
Reactant: COC(=O)c1ccc(F)c(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(N(C)c2cncnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium hydride (110 mg, 4.58 mmol, 1.10 eq) was dissolved in THF (10 mL), added to dry, argon purged flask, and cooled to 0° C. Compound 19 (1.0 g, 4.0 mmol, 1.0 eq) was dissolved in THF (10 mL) and added to sodium hydride solution. The reaction stirred at 0° C. for 30 minutes. Iodomethane (630 mg, 4.44 mmol, 1.10 eq) was added. The reaction warmed to rt and stirred overnight. Methanol was added and the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel afforded 600 mg (57%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.26 (s, 2H), 7.99 (dd, J=7.8, 2.0 Hz, 1H), 7.93 (ddd, J=8.5, 4.8, 2.2 Hz, 1H), 7.51 (dd, J=10.8, 8.7 Hz, 1H), 3.86 (s, 3H), 3.35 (s, 3H); ES-MS [M+1]+:262.1.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][C:30]=1[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][C:32]([O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:31][C:30]=1[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 2-(3-(((methylsulfonyl)oxy)methyl)phenoxy)acetate (94 mg) and 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (120 mg) in DMF (3.0 mL) was added potassium carbonate (67 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 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 (ethyl acetate/hexane) to give the title compound (102 mg) as a colorless oil.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:30][CH2:31]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(C)cc3)CC2)c(OC)nc1C
Yield: 87 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22].O>C(O)CCC>[S:17]1[CH:21]=[CH:20][N:19]2[C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:22]=[C:18]12
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: Nc1nccs1
Solvent: O
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (500 mg, 1.84 mmol) and thiazol-2-amine (370 mg, 3.68 mmol) in 1-butanol (22 mL) was heated at reflux overnight. The mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole as a yellow solid (350 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.16 (d, J=0.9 Hz, 1H), 6.99 (d, J=4.5 Hz, 1H), 6.71 (dd, J=0.9 Hz, J=4.5 Hz, 1H), 4.24 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 318 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][C:18]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][C:18]([C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:24])=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc(O)c4F)c23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A solution of 4-(2-fluoro-3-methoxyphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-137, 3.6 g, 7.82 mmol) in DCM (42 mL) was stirred at 0° C. and treated with boron tribromide (1 M in DCM, 94 mL, 94 mmol) and the mixture was stirred at rt overnight. The mixture was cooled again to 0° C. and treated slowly with methanol. The mixture was concentrated and purified by column chromatography on neutral alumina (eluting with 90:10 EtOAc-methanol) to provide 4-(2-fluoro-3-hydroxyphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a light colored solid (2.0 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.08 (s, 1H), 8.25 (br. s., 1H), 8.05 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.59 (br. s., 1H), 7.17 (m, 3H), 7.11 (d, J=7.6 Hz, 1H), 6.99 (dd, J=8.0, 1.2 Hz, 1H), 6.91 (t, J=7.2 Hz, 1H), 3.51 (br. s., 2H), 3.34 (m, 5H), 2.34 (br. s., 4H). Mass spectrum m/z 447.0 (M+H)+.