Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[N:24]=1>C(O)(=O)C.C1COCC1>[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:3]=[C:4]([NH:20][CH3:21])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[C:13]([F:19])[C:14]([F:18])=[C:15]([F:17])[CH:16]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[N:24]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)n1
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)n3)c(OC)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (80 mg, 0.255 mmol) was added to a solution of 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (86 mg, 0.383 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 120° C. for 4 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (15.5 mg, 0.025 mmol, 9.77% yield). LC-MS (M+H)+=502.0. 1H NMR (500 MHz, CDCl3) δ ppm 11.88-12.12 (1H, m), 8.63 (1H, s), 7.68-7.81 (1H, m), 7.60 (1H, s), 7.47 (1H, s), 6.92 (1H, t, J=7.2 Hz), 3.94-3.99 (1H, m), 3.52 (8H, s), 3.22-3.29 (1H, m), 2.87-3.01 (1H, m), 2.74-2.85 (1H, m), 2.22-2.38 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[Na].[N:15]12CCN(CC1)C[CH2:16]2.O>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:16]#[N:15])[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: C1CN2CCN1CC2
Reactant: Nc1nc(Cl)cc(-c2ccco2)n1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(-c2ccco2)nc(N)n1
Temperature: 0 °C
Reaction time: 96 h
Yield: 762.7 %

Procedure:
A solution of 2-amino-4-chloro-6-(2-furyl)pyrimidine (9.78 g, 50.0 mmol) in DMSO (200 mL) was treated with sodium cyamide (14.7 g, 300 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.56 g, 5.0 mmol). The suspension was stirred for 4 days, and more DABCO (5.04 g, 45 mmol) and DMSO (100 mL) were added. The suspension was stirred for a further 2 days, poured onto a mixture of ice (750 g) and water (750 mL), the crude product was filtered off, washed with water and MeCN, and dried in air to give the title compound (7.1 g, 77%) as a brown solid; m.p. 193-194° C.; NMR δH (400 MHz, DMSO) 6.74 (1H, q, J 1.6 Hz), 7.32 (2H, br s), 7.39 (1H, d, J 3.6 Hz), 7.43 (1H, s) and 7.98 (1H, d, J 1.2 Hz); M/Z 187 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:20])[C:17]([CH3:19])=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:20])[C:17]([CH3:19])=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:33][C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)[CH:10]=3
Reactant: Cc1cn2c3cc(Br)ccc3c3cc(O)cc(c1=O)c32
Reactant: ClCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn2c3cc(Br)ccc3c3cc(OCc4cccnc4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
9-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) produced in Example 114 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (315 mg) was added to the suspension. After stirring at room temperature for 30 minutes, 3-picolylchloride (137 mg) was added to the suspension. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (100 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (250 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:9])[N:6]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c1

Procedure:
prepared by reaction of 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccccc1-c1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(2-tolyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave the crude product which was purified by column chromatography giving the pure product (gum). This gum was dissolved in 5 ml of NH4OH, concentrated and dried under high vacuum to get the ammonium salt of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide in 67% yield, m.p. 180°-184° C. (NH3+ salt).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[NH:20][C:19](=[O:21])[C:18]2=[C:22]([CH3:28])[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[N:16]=1)[CH2:2][CH3:3].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].CN1C(=O)C2=CN=C(CCC)N2N=C1C1C(OCCC)=CC=C(S(N)(=O)=O)C=1>ClCCl.CO>[CH2:29]([N:31]([CH2:32][CH3:33])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:15]2[NH:20][C:19](=[O:21])[C:18]3=[C:22]([CH3:28])[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]3[N:16]=2)[CH:7]=1)(=[O:13])=[O:12])[CH3:30]
Reactant: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(CCC)nc(C)c2c(=O)[nH]1
Reactant: CCNCC
Agent: CCCOc1ccc(S(N)(=O)=O)cc1-c1nn2c(CCC)ncc2c(=O)n1C
Solvent: CO
Solvent: ClCCl
Product: CCCOc1ccc(S(=O)(=O)N(CC)CC)cc1-c1nn2c(CCC)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 22 mg (0.6 mmol) of diethylamine, 42 mg (92%) of N,N-diethyl-3-(5-(methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide are obtained. Rf=0.64 (dichloromethane/methanol=9:1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[Br:19]C1C=CC(C(C)(C)C)=C(O)C=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[Br:19][C:7]1[CH:2]=[CH:3][C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=1
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Br)cc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Using the same general procedure as for the preparation of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 8.18 g (35.7 mmol) of 5-bromo-2-t-butylphenol (Compound D), 0.90 g, 3.6 mmol) of pyridinium p-toluenesulfonate and 4.50 g (4.9 ml, 53.6 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane stirred at room temperature for 21 hours produced a dark yellow solution. At this time an additional 1.80 g (7.2 mmol) of pyridinium p-toluenesulfonate was added to the solution and it was allowed to stir at room temperature for 19 hours. After aqueous workup, a clear, yellow oil was isolated. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a clear, slightly yellow oil. PMR (CDCl3): d 1.38 (9H, s), 1.6-2.1 (6H, m), 3.65-3.75 (1H, m), 3.8-3.95 (1H, m), 5.45 (1H, t, J=2.5 Hz), 7.03 (1H, dd, J=8.4, 2.0 Hz), 7.13 (1H, d, J=8.4 Hz), 7.33 (1H, d, J=2.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[OH:18].[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[F-].[Cs+]>COCCOC.CO.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>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:7]2[CH:6]=[CH:5][C:4]([OH:18])=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:22][CH:21]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(-c2ccc(Br)cc2)ccc1O
Temperature: 70 °C
Yield: 54.1 %

Procedure:
A mixture of 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.250 g, 1.00 mmol), 1,4-dibromo benzene (0.259 g, 1.10 mmol), Pd(PPh3)4 (0.0580 g, 5%), and CsF (0.456 g, 3.00 mmol) in DME/MeOH (25 mL, 1:1) was heated at 70° C. overnight. The reaction mixture was concentrated and the residue was extracted with CH2Cl2, washed with water, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with hexane/CH2Cl2 (1:9) to give 0.151 g (54%) of the desired product. MS (DCI/NH3) m/z: 279.9 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 3.91 (s, 3H), 6.86 (d, J=8.14 Hz, 1H), 7.06 (m, 1H), 7.14 (d, J=2.03 Hz, 1H), 7.44-7.58 (m, 3H).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(O)cc23)CC1

Procedure:
To a solution of sodium (4.8 g; 210 mmol) in dry methanol (130 ml), there are added, at room temperature, 5-hydroxyindole (4 g; 30.04 mmol) and N-(tert-butoxycarbonyl)piperidone (8.9 g; 45.1 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=O)C.[CH3:41][NH2:42]>CO.C1COCC1>[CH3:41][NH:42][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 27 (b), 20 mg, 0.037 mmol) in 1 mL methanol was added a solution of methylamine in THF (2N, 2 mL). The mixture was stirred at 80° C. for 4 hours. The solvent was removed by vacuum to leave a yellow solid (17 mg, 87%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.60 (br, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 7.75 (s, 1H), 7.60 (br, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.20 (m, 2H), 7.12 (d, J=7.6 Hz, 1H), 6.87 (br, 2H), 3.69 (br, 4H), 3.01 (t, J=7.3 Hz, 2H), 2.94 (m, 5H), 2.65 (br, 2H), 2.49 (br, 6H), 2.17 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N6O3: 525.25 (M+H), Found 525.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[C:17]1[C:32]([NH2:34])=[O:33].CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH3:15])[C:17]=2[C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=1
Reactant: Cn1c(C(N)=O)c(-c2ccc(N)cc2)c2ccccc21
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(N)=O)c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2ccccc21
Reaction time: 1 h
Yield: 59 %

Procedure:
0.075 g of 2-fluoro-5-trifluoromethylphenyl isocyanate is added to a solution of 0.086 g of 1-methyl-3-(4-aminophenyl)-1H-indole-2-carboxamide in 18 ml of tetrahydrofuran and the stirring is continued for 1 hour. 5 ml of methanol are added, the reaction mixture is then concentrated under reduced pressure, and the residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume), to give 90 mg of 3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)ureido]phenyl}-1-methyl-1H-indole-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: O=C(Cl)c1ccoc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccoc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.061 mMol) 3-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[C:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])=[N-]>CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[C:1]1([C:7]2[C:17]([C:22]([O:24][CH3:25])=[O:23])([C:18]([O:20][CH3:21])=[O:19])[C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: C(#Cc1ccccc1)c1ccccc1
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Product: COC(=O)C1(C(=O)OC)C(c2ccccc2)=C1c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A 100 millilater round-bottom flask was equipped with a magnetic stirrer and reflux condenser with N2 inlet. The flask was charged with 25.0 grams (0.140 mole) of diphenylacetylene and 140 milligrams of cupric acetylacetonate. The mixture was heated to 120° C. using an oil bath and 8.85 grams (0.056 mole) of dimethyl diazomalonate was added over 24 hours using a syringe pump. When all of the dimethyl diazomalonate had been added, heating at 120° C. was continued for 8 hours. The diphenylacetylene was distilled off under vacuum, boiling point 170° C./19 Mm. The residue was purified by flash chromatography eluting with 75:25 hexane-ethyl acetate to give 4.65 grams (0.015 mole) of the desired product as a white solid. NMR analysis of the product indicated the following:
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes and then a solution of 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was used directly in the next step without purification (121 mg, 60%). LCMS calculated for C16H15Cl2N2O (M+H)+: m/z=321.0; Found: 321.0
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1Br.[C:21]1([O-:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1[O:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc(Br)c(O)c2c1C(=O)c1cc(Cl)ccc1C2=O
Reactant: [O-]c1ccccc1
Product: Nc1cc(Oc2ccccc2)c(O)c2c1C(=O)c1cc(Cl)ccc1C2=O

Procedure:
When 70.5 g of the 1-hydroxy-2-bromo-4-amino-6-chloroanthraquinone prepared above are subjected to a phenolate fusion as described in Example 467c, then 59 g, corresponding to 80% of theory, of 1-hydroxy-2-phenoxy-4-amino-6-chloroanthraquinone are obtained, the colour shade of which on silica gel is a pink tinged with blue having the Indicator Number 51 (Colour Index Hue Indication Chart).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCNCC2)cc1
Yield: 69.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(piperazin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.105 g; 0.302 mmol), piperazine (0.118 g; 1.36 mmol) and sodium iodide (0.229 g; 1.51 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 2 to 16% methanol in dichloromethane) furnished 0.083 g (69%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=O)[C@H:9]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:39])[C@H:9]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2NC1=S)OCc1ccccc1

Procedure:
A mixture of (+)-phenylmethyl N-[(3R)-2,3-dihydro-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate (4.0 g, 10 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (4.5 g 11 mmol) in toluene (100 mL) was heated under reflux for 75 min. The mixture was cooled and the volume was reduced to 30 mL by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (75:25) to give phenylmethyl N-[(3R)-2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[CH:8]=[C:3]([CH2:2][O:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:4]=2)=[CH:17][CH:18]=1)=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1,1-dimethyl-urea (384 mg) was dissolved in DCM (12 mL) and triethylamine (0.216 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.121 mL) and the reaction was stirred for 15 minutes at RT before being concentrated in vacuo to give the desired material.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:6])=[O:5].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>C(#N)C.O>[CH3:1][N:2]([CH3:17])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:25]([NH:26][C:27]1[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=1)=[O:24])(=[O:15])=[O:14])(=[O:6])=[O:5]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CN(C)NS(=O)(=O)c1ccccc1S(N)(=O)=O
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)NN(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
To a solution of 0.14 g of the product of Example 1 and 0.15 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate in 2 mL of dry acetonitrile was added 0.1 mL of 1,5-diazabicyclo[5.4.0]undec-5-ene. The solution was stirred for 15 minutes at room temperature, diluted with 2 mL of water and acidified with 5% hydrochloric acid to a pH of 4. The precipitated product was collected by filtration, washed thoroughly with water, washed with 1-chlorbutane, and dried in vacuo at 40° C. to afford 0.02 g of the subject compound, m.p. 127°-128° C. (dec).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.O.[NH3:12]>O>[NH2:12][C:2]1[N:3]=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)c1ccc(Cl)nn1
Solvent: O
Product: CC(C)c1ccc(N)nn1
Temperature: 165 °C

Procedure:
3-Chloro-6-isopropylpyridazine (1.60 g, 10.2 mmol) and 28% ammonia water (15.0 ml) were introduced into a sealed tube reactor and stirred under pressure and heating at 140° C. for 24 hours and at 165° C. for 25 hours. The reaction solution was left and cooled, poured into water (30.0 ml), adjusted to pH 9, and extracted 3 times with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude crystals. The crystals, while being washed with diisopropyl ether-hexane, were filtered to give the title compound as pale brown crystals. The yield was 0.41 g (29.3%).