Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1.[O-]CC.[Na+].[CH3:21][C:22]([CH:24]=[CH2:25])=[O:23].Cl>C(O)C>[O:23]=[C:22]1[CH2:24][CH2:25][C:3]2[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=2[CH2:21]1
Reactant: C=CC(C)=O
Reactant: O=C1Cc2ccccc2Oc2ccccc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
To a solution of 42 g of the compound 10-keto-10,11-dihydrodibenzo(b,f)-oxepine in 200 ml of dry ethanol a solution of sodiumethoxide (7 g of sodium in 500 ml of ethanol) is added dropwise. After stirring the mixture for 30 minutes 16.2 ml of methylvinylketon in 50 ml of ethanol are added, whereupon the solution is refluxed for 1 hour. The solution is cooled then and poured into 2 N HCl. After extracting into ether, washing the ether layer with water (till neutral) and drying the etherial phase, the solvent is evaporated.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Si:14]([O:31][CH2:32][C@@H:33]([N:36]1[C@H:41]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@:38]([CH3:58])([CH:56]=O)[C:37]1=[O:59])[CH2:34][CH3:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Si:14]([O:31][CH2:32][C@@H:33]([N:36]1[C@H:41]([C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@@:38](/[CH:58]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])([CH3:56])[C:37]1=[O:59])[CH2:34][CH3:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(/C=C/C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of THF (4 mL) and sodium hydride (16 mg, 0.40 mmol, 60% dispersion in oil) under a nitrogen atmosphere at 0° C. was added trimethyl phosphonoacetate (61 μL, 0.43 mmol) dropwise over 30 seconds. The mixture was allowed to warm to rt for 30 minutes. A solution of (3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carbaldehyde (205 mg, 0.305 mmol; Example 248, Step C) in THF (3 mL) was added. The resulting mixture was stirred at rt for 2 hours. The reaction was partitioned between EtOAc (80 mL) and water (40 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (SiO2, hexanes:EtOAc, 1:0 to 8:2) gave the title compound. Mass Spectrum (ESI) m/z=728.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[O:2][CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)cccc1F
Reactant: COC1CCCCC1O
Product: COC1CCCCC1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from 2-methoxycyclohexanol and 2-amino-6-fluorobenzonitrile as a yellow oil (34%). MS 247 (MH+).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH3:19])[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[CH3:30][O:31][C:32]1[C:37]([NH2:38])=[CH:36][CH:35]=[CH:34][N:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:18]([NH:17][C:15]2[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=[C:11]([NH:38][C:37]3[C:32]([O:31][CH3:30])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:16]=2)[CH3:19])=[N:21][CH:22]=1
Reactant: C[C@H](Nc1nc(On2nnc3ccccc32)ncc1C(N)=O)c1ccc(F)cn1
Reactant: COc1ncccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1Nc1ncc(C(N)=O)c(N[C@@H](C)c2ccc(F)cn2)n1
Yield: 68.5 %

Procedure:
A solution of (S)-2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-(5-fluoropyridin-2-yl) ethyl amino)pyrimidine-5-carboxamide (Preparation 5c, 30 mg, 0.08 mmol), 2-methoxy pyridin-3-amine (14 mg, 0.11 mmol) and p-toluenesulfonic acid hydrate (15 mg, 0.08 mmol) in 1,4-dioxane (3 mL) was heated at 120° C. for 4 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (21 mg, 72%) as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[C:32]([S:51][CH2:52][CH2:53][NH2:54])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:54][CH2:53][CH2:52][S:51][C:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]2)c1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (940 mg, 2.1 mmol) synthesized in Example (18a), 2-(tritylthio)ethaneamine (1.01 g, 3.17 mmol) synthesized in Example (25a) and 4-dimethylaminopyridine (13 mg, 0.1 mmol) were added, followed by dissolution in dichloromethane (50 mL), and subsequently WSCI•HCl (445 mg, 2.3 mmol) was added at room temperature, and stirring was carried out for 1 hour under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (150 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-55%) to afford the desired product (1.08 g, yield 69%) as a white solid.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[C:22]=1[CH3:23].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([NH:27][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:28]=[CH:29][CH:30]=2)[C:22]=1[CH3:23]
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc4c3Cc3ccccc3-4)c2)c1C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a suspension of 9H-fluorene-1-carboxylic acid (106 mg) and 3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (123 mg, 64.7%).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:36][C:34]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:35]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCN(CCN2CCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 4.5 h
Yield: 81.6 %

Procedure:
After adding tetrahydrofuran (3 ml) and methanol (3 ml) to a crude product of 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (129 mg) under a nitrogen atmosphere, 10% palladium-carbon (60 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 4.5 hours. The atmosphere in the reaction vessel was then replaced with nitrogen, and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=19:1), and then Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of the title compound (98.4 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH:16]1([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH:16]1([N:19]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:17][CH2:18]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methyl-oxazol-5-yl)-benzoyl chloride (89 mg) is added portionwise to a mixture of cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine (100 mg) and ethyldiisopropylamine (100 μL) in dichloromethane (5 mL). The mixture is stirred for 1 h at room temperature, washed with water and 1 M HCl, dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 6): tR=1.83 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:24][NH:23][C:21]([C:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:28][CH:29]5[CH2:31][O:30]5)=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:14][C:15]=2[O:19][C:18]=1[CH3:20])=[O:22]
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCC5CO5)ccc34)ccc12
Yield: 93.8 %

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 123-A (1 g, 2.9 mmol), 2-(bromomethyl)oxirane (467 mg, 3.4 mmol) and Cs2CO3 (1.4 g, 4.2 mmol) in CH3CN (25 ml) was heated to 65° C. for 3 hours. The solution was extracted with EtOAc. N,2-dimethyl-6-{[7-(oxiran-2-ylmethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 123-B (1.1 g) was isolated by a silica gel column using 1-5% MeOH in CH2Cl2. To a solution of 123-B (150 mg, 0.35 mmol) in THF (5 ml) was added a solution of methylamine in MeOH (1N, 1 ml). The solution was heated to 65° C. for 2 hours. The crude product was purified by HPLC (10-40% CH3CN/H2O over 30 min.) to give 6-({7-[2-hydroxy-3-(methylamino)propoxy]quinolin-4-yl}oxy)-N,2-dimethyl-1-benzofuran-3-carboxamide 123.
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[NH:20]1[C:24]2=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=[C:23]2[CH:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([NH:29][C:27]1[CH:28]=[C:23]2[CH:22]=[CH:21][NH:20][C:24]2=[N:25][CH:26]=1)=[O:6]
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
2,6-Difluoro-3-(N-propylsulfamoylamino)benzoic acid (0.095 g, 0.32 mmol), 1H-pyrrolo[2,3-b]pyridin-5-amine (0.043 g, 0.32 mmol), HOBt (0.044 g, 0.32 mmol), and EDCI (0.062 g, 0.32 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (30 mL) and washed with a mixture of 1:1:1 water:bicarbonate:brine (3×20 mL). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography eluting with 1:1 then 8:2 EtOAc:hexanes to provide 2,6-difluoro-3-(N-propylsulfamoylamino)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.060 g, 0.15 mmol, 45% yield). 1H NMR (400 MHz, CD3OD) δ 8.36-8.40 (m, 2H), 7.64-7.72 (m, 1H), 7.41-7.43 (m, 1H), 7.06-7.13 (m, 1H), 6.50-6.52 (m, 1H), 2.96-3.02 (m, 2H), 1.47-1.57 (m, 2H), 0.87-0.93 (m, 3H); m/z (APCI-pos) M+1=410.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18]O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(Cl)(Cl)(Cl)[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][Cl:21])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: ClCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C

Procedure:
3.56 g (12.9 mmol) of 3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol was suspended in 30 ml of methylene chloride, and carbon tetrachloride (30 ml) and triphenyl phosphine (4.06 g, 15.5 mmol) were added thereto followed by stirring under reflux for 3 hours. The reaction mixture was cooled to room temperature, then methanol and methylene chloride were added thereto so as to make the mixture uniform. Silica gel (30 g) was added to the uniform solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 300 g, n-hexane:ethyl acetate=2:1), then concentrated under reduced pressure to obtain 1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (2.36 g) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH2:8][C:7]=1[C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=1.[CH3:13][N:14]([CH2:18][CH2:19]Cl)[CH2:15][CH2:16]Cl.Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:7]12[CH2:8][C:4](=[CH:3][C:2]=1[N:1]1[CH2:19][CH2:18][N:14]([CH3:13])[CH2:15][CH2:16]1)[C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]2=1
Reactant: CN(CCCl)CCCl
Reactant: NC1=C2CC(=C1)c1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CCN(C2=C3CC(=C2)c2ccccc23)CC1

Procedure:
2-Aminobenzobicyclo[2.2.1]heptene (1.1 g) was combined with mechlorethamine hydrochloride (1.4 g), potassium carbonate (1.5 g), and acetonitrile (25 ml) and heated to reflux for 24 hours. Water (50 ml) was added to the mixture and the resulting mixture was extracted with ether (3×50 ml). The combined ether solutions were dried over magnesium sulfate and the ether was removed on a rotary evaporator. The residue was combined with concentrated hydrochloric acid (5 ml) and 2-propanol (25 ml) and the solvent was removed on a rotary evaporator. The residue was suspended in 2-propanol and the solvent was removed on a rotary evaporator. This latter step was repeated. The residue was recrystallized from 2-propanol to provide the product as a tan solid. Analytical data are reported in Table I.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21](F)=[C:22]([CH:25]=3)C#N)=[N:14][C:12]=2[N:13]=1.O.[NH2:35]N>CCO>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[C:22]([NH2:35])[CH:21]=[CH:20][CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccc(F)c(C#N)c3)nc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3cccc(N)c3)nc2n1

Procedure:
To a 0.3M solution of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (example lay) (1 equiv) in EtOH was added hydrazine hydrate (5 equiv). The mixture was refluxed for 90 minutes whereupon it was cooled and partitioned between CH2Cl2 and water (1 reaction volume of each). The organic extract was removed. The aqueous phase was further extracted with CH2Cl2 (2×1 reaction volume). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a yellow slurry which was further purified by flash chromatography (SiO2) using EtOAC/Hexanes as eluent to give the title compound as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[N:6]=[C:5]2[CH3:11]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-3-methylindazole 104 (0.2 g, 0.948 mmol) in anhydrous THF (3 mL), cooled in ice bath, was added potassium t-butoxide (0.127 g, 1.13 mmol) and 4-methoxybenzyl chloride (0.14 mL, 1.04 mmol). The reaction mixture was allowed to warmed to room temperature and was stirred for 16 hours. Ethyl acetate (100 mL) was added and the organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-N-(4-methoxybenzyl)-3-methylindazole 105 (0.29 g, 0.932 mmol) as a mixture of the 1H- and 2H-indazole regioisomers.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCCCC2)cc1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with piperidine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((piperidin-1-yl)methyl)benzamide. MS (Q1) 406.4 (M)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccc5[nH]ccc45)c3)c(=O)oc12
Temperature: 25 °C
Yield: 67.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-4-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.018 g of product in 70% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)[C:6](=[S:25])[NH:5][C:4](=[O:26])[C:3]=1[NH:27][C:28](=O)[C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:31])[CH3:30].CC([O-])(C)C.[K+]>C(O)(C)C.ClCCl>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH2:8][N:7]1[C:2]2[N:1]=[C:28]([C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([CH3:30])[CH3:31])[NH:27][C:3]=2[C:4](=[O:26])[NH:5][C:6]1=[S:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(Cn2c(N)c(NC(=O)C(C)(C)OCc3ccccc3)c(=O)[nH]c2=S)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]c(C(C)(C)OCc4ccccc4)nc32)cc1OCc1ccccc1
Yield: 69.9 %

Procedure:
6-Amino-1-(3 -benzyloxy-4-methoxy-benzyl)-5-(2-benzyloxy-2-methyl-propionylamino)-2-thiouracil (46.54 g, 83 mmole) and 97% t-BuOK (38.41 g, 332 mmole) were heated under reflux in isopropanol (460 ml) for 50 minutes. The solvent was removed in vacuo, the residue dissolved in water (300 ml), treated twice with 5 g of charcoal, filtered, water added to a total volume of 500 ml and pH adjusted to neutral with a mixture of 5M HCl (60 ml) and sodium bicarbonate solution. The solid was collected at 10° C. to give 41.62 g of crude product, which was dissolved in dichloromethane (60 ml) and chromatographed over silicagel (126 g) using dichloromethane as eluant. Crystallization from methanol gave 3-(3-benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-2-thioxanthine, (31.5 g, 69.9%) mp 290-302° C. (dec).