Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16](=S)[C:15]3[CH:25]=[CH:26][CH:27]=[N:28][C:14]2=3)=[O:12])[CH2:6][CH2:5]1.[C:29](OCC)(=[O:32])[NH:30][NH2:31]>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]3[C:29](=[O:32])[NH:30][N:31]=[C:16]3[C:15]3[CH:25]=[CH:26][CH:27]=[N:28][C:14]2=3)=[O:12])[CH2:6][CH2:5]1
Reactant: O=C(CN1CCN(CCO)CC1)N1c2ccccc2NC(=S)c2cccnc21
Reactant: CCOC(=O)NN
Product: O=C(CN1CCN(CCO)CC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-[[4-(2-hydroxyethyl)-piperazino]acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].C(N(CC)CC)C.[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35](Cl)=[O:36])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.O>C1COCC1>[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35]([O:14][C:12]3[CH:11]=[CH:10][C:3]([C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[C:2]([F:1])[CH:13]=3)=[O:36])[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: C=CCOC(=O)c1ccc(O)cc1F
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1ccc(OC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
To a mixture of 1.96 g (10 mmoles) of allyl 2-fluoro-4-hydroxybenzoate, 1.53 ml (11 mmoles) of triethylamine and 25 ml of THF, there is slowly added a solution of 3 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 50 ml of THF. The reaction medium is stirred at ambient temperature for 12 hours and then poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column, eluted by a 50:50 mixture of dichloromethane and hexane. After evaporation of the solvents, 3.63 g (78% yield) of the expected ester having a melting point of 102°-104° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[I:11]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[C:7]=1[I:11]
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1nc(Cl)cc(N)c1=O
Solvent: CC#N
Product: Cn1nc(Cl)c(I)c(N)c1=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of Example 74a (2.12 g, 13.3 mmol) and N-iodosuccinimide (5.38 g, 23.9 mmol) in acetonitrile (30 mL) was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-40% ethyl acetate in hexanes to afford 3.27 g (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(Nc2nc(Cl)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (300 mg, 1.45 mmol) and 3-(trifluoromethyl)benzenamine (304.8 mg, 1.89 mmol) in 10 mL of DMSO was added DIEA (282 mg, 2.18 mmol) in one portion at room temperature. Then the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 40 mL of water, and the solid obtained was filtered, rinsed with water, and dried. The desired product 5-chloro-N-(3-(trifluoromethyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine was obtained (356 mg, 74%) as a yellow solid. LC-MS: 331.0 [M+H]+, tR=1.70 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([F:14])=[CH:4][N:3]=1.[CH3:15][O:16][C:17](=[O:29])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[CH3:15][O:16][C:17](=[O:29])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:12][CH2:11][CH2:10][CH2:9][N:8]([C:6]3[C:5]([F:14])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH3:13])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: COC(=O)Cn1ccc2cc(O)ccc21
Reactant: CN(CCCO)c1nc(Cl)ncc1F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(Cl)ncc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-1-propanol (Example 83, 0.60 g, 2.73 mmol) and methyl(5-hydroxy-1H-indol-1-yl)acetate (Example 9, 0.37 g, 1.82 mmol) in dichloromethane (9 mL) was added triphenylphosphine (0.70 g, 2.73 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.72 g, 2.73 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h. The desired product (0.42 g, 56%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 7.85 (d, 1H), 7.15-7.07 (m, 3H), 6.88-6.83 (m, 1H), 6.47-6.46 (m, 1H), 4.85 (s, 2H), 4.07 (t, 2H), 3.84 (t, 2H), 3.76 (s, 3H), 3.26 (d, 3H), 2.20-2.13 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:23]([C:45]4[CH:57]=[CH:56][C:55]5[C:54]6[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=6)[C:48]([CH2:62][CH2:63][CH2:64][CH3:65])([CH2:58][CH2:59][CH2:60][CH3:61])[C:47]=5[CH:46]=4)[C:24]4[CH:36]=[CH:35][C:34]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[C:27]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[C:26]=5[CH:25]=4)=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH:66]([C:68]1[S:72][C:71](B(O)O)=[CH:70][CH:69]=1)=[O:67]>>[CH2:37]([C:27]1([CH2:41][CH2:42][CH2:43][CH3:44])[C:26]2[CH:25]=[C:24]([N:23]([C:9]3[CH:8]=[CH:7][C:6]4[C:5]5[C:13](=[CH:14][CH:2]=[CH:3][CH:4]=5)[C:12]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=4[CH:10]=3)[C:45]3[CH:46]=[C:47]4[C:55]([C:54]5[CH:53]=[CH:52][C:51]([C:71]6[S:72][C:68]([CH:66]=[O:67])=[CH:69][CH:70]=6)=[CH:50][C:49]=5[C:48]4([CH2:58][CH2:59][CH2:60][CH3:61])[CH2:62][CH2:63][CH2:64][CH3:65])=[CH:56][CH:57]=3)[CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(Br)ccc3-4)cc21
Reactant: O=Cc1ccc(B(O)O)s1
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(-c5ccc(C=O)s5)ccc3-4)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1>C(O)(=O)C>[C:1]([O:6][OH:6])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:4][CH2:3][CH2:2][CH2:1][CH2:4][CH2:3][CH2:2][C:1]([O:6][OH:7])=[O:7]
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C(CCCCCCCCCCC(=O)OO)OO

Procedure:
a mixture of maleic anhydride, a urea-hydrogen peroxide complex and acetic acid; and
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(=O)C(C)C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)ccc1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the above prepared 1-(2-hydroxy-4-methoxy-phenyl)-2-methyl-propan-1-one (5.43 g, 28 mmol) in 56 mL acetonitrile were successively added Cs2CO3 (10.9 g, 1.2 eq.) and ethyl bromoacetate (3.25 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 2.5 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left 8.01 g of the title product as light yellow oil, sufficiently pure to be used for the next step.
Reaction SMILES: [C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1)[CH2:4][NH2:5])#[N:2].C[Si]([N:24]=[C:25]=[O:26])(C)C.[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:7]=1)[CH2:4][NH:5][C:25]([NH2:24])=[O:26])#[N:2]
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1ccc(C(C#N)CN)cc1OC1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)CNC(N)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine [3-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrile, 0.17 g, 0.66 mmol] in tetrahydrofuran (5 mL) under an argon atmosphere was added trimethylsilyl isocyanate (0.13 mL, 0.96 mmol). The resulting mixture was stirred overnight at room temperature. Aqueous ammonium chloride was added, the mixture was extracted three times with 5% methanol/methylene chloride, the extract was dried (potassium carbonate) and evaporated. Purification of the residue by flash chromatography, eluting with 4% methanol/methylene chloride, provided the urea as a white solid: m.p. 55°-61° C. (sublimes).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[CH2:30](Cl)Cl.C(N([CH2:38][CH3:39])CC)C.[BH4-].[Na+]>O>[CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[CH2:13][CH2:14]2)[CH2:3][CH2:2][CH2:39][CH2:38][CH2:30]1
Reactant: Clc1ccc2c(NCCCN3CCN(CCCNCC4CC4)CC3)ccnc2c1
Reactant: ClCCl
Reactant: CCN(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(NCCCN3CCN(CCCNCC4CCCCC4)CC3)ccnc2c1
Reaction time: 3 h

Procedure:
To a solution of N4-3-[4(3-aminopropyl)piperazine]propyl-7-chloroquinolin-4-amine (Intermediate of example 12) (150 mg, 0.41 mmol) in CH2Cl2 (4 mL) cyclohexane-1-carboxaldehyde (83 μL, 0.46 mmol), triethylamine (26 μL, 0.16 mmol) and 3 Å molecular sieves are added. The reaction media is stirred for 3 h and cooled before NaBH4 (78 mg, 2.05 mmol) is added portionwise over 30 min. Stirring is left for 1.5 h, water (10 mL) is added and the media is filtered. Compound is extracted with CH2Cl2 (3×20 mL). Combined organic layers are dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH:90/10/1.4).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23](B(O)O)=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:7]3[C:6](=[CH:11][C:10]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][C:24]=4[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:9][CH:8]=3)[C:5]([CH3:16])([CH3:17])[C:4]=2[CH:3]=1
Reactant: COc1ccc(B(O)O)c(-c2ccccc2)c1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)c2cc(Br)ccc2-3)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 75 %

Procedure:
A mixture of 3.52 g (10 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 2.75 g (12 mmol) of 5-methoxybiphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (3.4 g, 7.5 mmol, 75%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[C:31]([F:39])[C:32]([F:38])=[C:33]([F:37])[C:34]=3[F:36])[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([C:42]([N:41]([CH3:45])[CH3:40])=[O:43])[CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[C:31]([F:39])[C:32]([F:38])=[C:33]([F:37])[C:34]=3[F:36])[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)[C@H]1CNCCN1S(=O)(=O)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Reaction time: 14 h
Yield: 67 %

Procedure:
A solution of N-benzyloxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (12 g, 21.08 mmol) [prepared as described in Step 5 above] and 2,6-luitidine (4.0 ml, 33.73 mmol) in methylene chloride (100 ml) was treated with dimethylcarbamoyl chloride (3.10 ml, 33.73 mmol) and stirred for 14 h. The reaction mixture was washed with 3M aqueous HCl solution (20 ml), brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane then 5% methanol/methylene chloride). The product was dissolved in ethyl acetate (25 ml) and added dropwise to hexane (200 ml) with vigorous stirring. The solid was filtered to give N-benzyloxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1sulfonyl]piperazine-2-(R)-carboxamide (67%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22]C)[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:3][CH3:4].CO>O>[CH2:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:3][CH3:4]
Reactant: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: CO
Solvent: O
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Yield: 13.7 %

Procedure:
Add 3N hydrochloric acid (1 cc.) to a solution of 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.61 g.) in boiling methanol (70 cc.) and cool the mixture immediately and allow to stand for 41/2 hours. Pour the product into water (300 cc.) and extract the mixture with ether; work up in the usual way to give as residue an amorphous solid (0.6 g.). Crystallize this solid from a mixture of ether and hexane. Take up the resulting solid in benzene (20 cc.) and chromatograph on a column of neutral alumina. Elute the product with ether and recrystallize from a mixture of ether and hexane to obtain 13β-n-propyl-17β-hydroxy-gon-4-en-3-one (0.08 g.), mp. 126°-7°; ultraviolet absorption peak at 240 mμ (ε15,000); infrared absorption peaks at 2.92, 6.01, 6.20 μ. Evaporation of the mother liquors gives a second, polymorphic, form of the same substance (0.17 g.), m.p. 144°-5° , having ultraviolet and infrared spectra identical with the first material; a mixture of the two forms has m.p. 144°-5°.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[C:18](Cl)(=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:30]([C:31]1[O:16][C:8](=[O:17])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCc1nc2ccccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (1.76 ml) was added to a suspension of anthranilic acid (823 mg) in methylene chloride (20 ml). Then, myristoyl chloride (1.63 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 2.5 hour at room temperature, the reaction mixture was cooled with ice. Triethylamine (0.92 ml) and ethyl chlorocarbonate (0.63 ml) were dropwise added to the reaction mixture successively. After being stirred for 1 hour at 0° C. and for 1.5 hours at room temperature successively, the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with water, neutralized with diluted hydrochloric acid, and washed with saturated brine. The organic layer was dried over magnesium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 60 g, chloroform-hexane), thereby yielding 1.663 g of the aimed compound as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=1
Reactant: COC(=O)c1ccc2nc[nH]c(=O)c2c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ncn(Cc3cccc(C(F)(F)F)c3)c(=O)c2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate (30.6 mg, 0.15 mmol) in DMF (2 mL) was added potassium carbonate (41.5 mg, 0.30 mmol) and 3-(trifluoromethyl)benzyl bromide (45.8 μL, 0.30 mmol). The reaction mixture was heated to 60° C. and stirred overnight. The mixture was then cooled to rt and concentrated. Water was added and the reaction mixture was extracted with DCM (5 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazoline-6-carboxylate. LC-MS: (FA) ES+ 363.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][NH:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.CCOCC>[CH2:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CNCCC1=O
Reactant: BrCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCC1CN(CCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 3-Butyl-piperidine-4-one (250 mg) in DMF (5 ml) was added DIPEA (468 mg) and then a solution of (2-bromoethyl)-benzene (373 mg) in DMF (5 ml) over a period of 45 min. The resulting mixture was stirred at RT for 1 hour and then heated to 60° C. for 6 hours. The reaction mixture was cooled, diluted with ether and the organic solution was washed with 10% aq. Na2CO3 solution twice and brine. The organic layer was dried over MgSO4, filtered and evaporated to give a residue which was purified by flash chromatography (ethyl acetate/hexanes 1:3) to give the product as a colorless liquid (355 mg). MS (ESI): 260.4 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:48]=[CH:47][C:43](C(O)=O)=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.C1(P([N:63]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:41]=[CH:42][C:43]([NH2:63])=[CH:47][CH:48]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 31.5 %

Procedure:
A mixture of 100 mg 4-{4-[3-(2-pyridyl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-3-pyrazolyl}benzoic acid obtained in Example 48, 44 mg diphenyl phosphoryl azide, 23 mg potassium carbonate, and 4 mL N,N-dimethylformamide was stirred at 80° C. for 6 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed twice with water and then with brine, and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was evaporated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), to give 30 mg of the title compound as a pale yellow amorphous.