Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[N:4]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20](COC)[C:19]([C:25]1[N:29]=[CH:28][N:27]([CH3:30])[N:26]=1)=[CH:18]2)[S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6].Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:30][N:27]1[CH:28]=[N:29][C:25]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:4][S:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)(=[O:6])=[O:7])=[N:26]1
Reactant: COCN(c1cccc2cc(-c3ncn(C)n3)n(COC)c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1cnc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Yield: 20.8 %

Procedure:
N-(Methoxymethyl)-N-[1-(methoxymethyl)-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.42 g), concentrated hydrochloric acid (1 mL) and methanol (6 mL) were heated under reflux for 6 hr. The reaction mixture was neutralized with aqueous sodium bicarbonate, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.07 g, yield 20%) as colorless crystals. The crystals were recrystallized from ethyl acetate. melting point>161° C. (decomposition).
Reaction SMILES: C(S[C:9]1[NH:10][CH2:11][CH2:12][N:13]=1)C1C=CC=CC=1.[CH3:14][CH:15]([CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]1)[CH3:16]>ClCCl.C1N2CCN(CC2)C1>[CH3:16][CH:15]([CH:17]1[CH2:18][C:19](=[O:24])[C:20](=[C:9]2[NH:13][CH2:12][CH2:11][NH:10]2)[C:21](=[O:23])[CH2:22]1)[CH3:14]
Reactant: CC(C)C1CC(=O)CC(=O)C1
Reactant: c1ccc(CSC2=NCCN2)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CC(C)C1CC(=O)C(=C2NCCN2)C(=O)C1
Reaction time: 7.1 h
Yield: 14.5 %

Procedure:
A mixture of 2-benzylthio-4,5-dihydro-1H-imidazole (15.4 grams, 0.08 mole), 5-(1-methylethyl)-1,3-cyclohexanedione (12.3 grams, 0.08 mole) and 0.11 gram of DABCO is heated at 115°-120° C., with stirring, for a period of 7.1 hours. The cooled residue is dissolved in dichloromethane and the solution extracted with three portions of 3N sodium hydroxide, then with four portions of 3N hydrochloric acid. The organic phase is then dried over magnesium sulfate and evaporated, to give 15.31 grams of crude product as a yellow solid. The material is recrystallized twice from toluene and once from ethyl acetate, to give 2.58 grams of product, m.p. 223°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](Cl)([Cl:13])=[O:12]>>[Cl:13][C:11]([O:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])=[O:12]
Reactant: O=C(Cl)Cl
Reactant: CC(O)c1ccc(Cl)cc1
Product: CC(OC(=O)Cl)c1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 1-(4-chlorophenyl)ethanol and phosgene (20% in toluene).
Reaction SMILES: CC(C)([O-])C.[Na+].[O:7]=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[NH:9]1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.Cl>CN1CCCC1=O.O>[CH3:20][O:19][C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([OH:7])=[C:16]2[C:22]1[C:23]2[CH:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1)=[O:18]
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Clc1ncnc2sccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ncnc4sccc34)c2c1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
Sodium tert-butoxide (40.3 mg, 0.42 mmol) and methyl 2-oxo-5-indolinecarboxylate (17.6 mg, 0.092 mmol) in N-methylpyrrolidinone (1 mL) under nitrogen atmosphere were stirred for 5 min at room temperature. A solution of 4-chlorothieno[2,3-d]pyrimidine (0.1 mL, 0.84 M, corresponding to 14.3 mg, 0.084 mmol) in N-methylpyrrolidinone was added and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with water (20 mL) and acidified with hydrochloric acid (1 M) and extracted with ethyl acetate (2×15 mL). The combined organic layer was washed with brine, dried with sodium sulphate, filtered and concentrated. The crude product was triturated with methylene chloride to give 10 mg (36% yield) of the title compound as a bronze solid. MS (AP−) m/z 324 (M−1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH2:33][OH:34])=[CH:23]2)=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH:33]=[O:34])=[CH:23]2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A mixture of [1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]methanol (1.15 g), active manganese dioxide (2.30 g) and ethyl acetate (80 ml) was stirred at room temperature for 2 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenylpyrrole-3-carbaldehyde (1.06 g, yield 93%) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and benzoyl chloride (55 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[C:19]1([NH:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([NH:28][CH2:27][CH2:26][NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: NCCNc1ccccc1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(NCCNc3ccccc3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile and phenylethylenediamine in DME. ES-MS m/e (%): 335 (M+H+, 100), 242 ([M+H-PhNH2]+, 30).
Reaction SMILES: [O:1]([C@@H:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]([N:16]([CH:36]([CH3:38])[CH3:37])[CH2:17][CH2:18][CH:19]([C:26]1[CH:31]=[C:30]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:28][C:27]=1[OH:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:15])[CH3:14]>C(OCC)(=O)C>[O:1]([C@@H:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18][C@@H:19]([C:26]1[CH:31]=[C:30]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:28][C:27]=1[OH:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:38])[CH3:37]
Reactant: CC(C)N(CCC(c1ccccc1)c1cc(CCO)ccc1O)C(C)C
Agent: C[C@H](Oc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCO)ccc1O)C(C)C
Temperature: 80 °C
Yield: 36.5 %

Procedure:
(S)-2-Phenoxypropionic acid (3.40 g, 20.5 mmol, 1 equiv) was added to a solution of 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(2-hydroxyethyl)phenol (Example 9, 7.28 g, 20.5 mmol, 1 equiv) in ethyl acetate. The mixture was heated at 80° C. for 2 days, upon which the mixture was cooled to room temperature, filtered and washed with ethyl acetate and dried in vacuo at 50° C. overnight to give the title compound as a white solid (3.9 g, 7.48 mmol, 37% yield, 94% ee).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:33][CH2:34][OH:35])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:33][CH:34]=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: COC(=O)CCC(CCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(CC=O)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.47 mL dimethylsulfoxide in 19 mL methylene chloride is cooled to -70° C. and 0.41 mL oxalyl chloride is added slowly. The solution is stirred at -70° C. for 15 minutes and a solution of 0.38 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)octanoate in 1 mL methylene chloride is added slowly. The solution is stirred at -60° C. for 15 minutes and 1.9 mL triethylamine is added. The mixture is allowed to warm up to room temperature, washed with saturated sodium bicarbonate solution, and the organic phase is dried, filtered and evaporated to obtain a yellow oil. This oil is taken up in ether and washed with saturated sodium bicarbonate solution. The ether layer is dried, filtered and evaporated to yield methyl 8-(p-chlorophenylsulfonamido)4-(formylmethyl)-octanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([S:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH:16]=[CH:15][N:14]=1
Reactant: Sc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2c(Cl)cccc2Cl)ccn1
Yield: 49.8 %

Procedure:
Using the method of Example 3, Step A, 2,6-dichlorobenzenethiol (1.69 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(2,6-dichlorophenylthio)pyridine (1.37 g, 50% yield) as a white powder. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.53 (d, 2H), 7.41 (t, 1H), 6.84 (s, 1H), 6.79 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH:18]1[CH2:23][CH2:22][N:21](C(OCC)=O)[CH2:20][CH2:19]1)[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2ccccc2Cl)CC1
Agent: Br
Product: O=C(Cc1ccccc1)N(c1ccccc1Cl)C1CCNCC1

Procedure:
A mixture of 20 parts of ethyl 4-[N-(2-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate and 300 parts of hydrobromic acid solution 48% is stirred and refluxed for 1h.10. The hydrobromic acid solution 48% is removed in vacuo and to the residue is added successively water and sodium hydroxide solution. The free base is extracted with trichloromethane. The latter is dried and evaporated. The solid residue is washed with 1,1'-oxybisethane and dried, yielding 10.6 parts of N-(2-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide; mp. 135.5° C.
Reaction SMILES: [NH:1]([C:8]1[S:12][N:11]=[C:10]([C:13]([Cl:16])([Cl:15])[Cl:14])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[C:2]1([N:1]([C:8]2[S:12][N:11]=[C:10]([C:13]([Cl:16])([Cl:15])[Cl:14])[N:9]=2)[C:19](=[O:20])[C:18]([Cl:23])([Cl:22])[Cl:17])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)c1nsc(Nc2ccccc2)n1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(N(c1ccccc1)c1nc(C(Cl)(Cl)Cl)ns1)C(Cl)(Cl)Cl
Yield: 90.9 %

Procedure:
A solution of 14.7 grams (0.05 mole) 5-anilino-3-trichloromethyl-1,2,4-thiadiazole and 18.0 grams (0.1 mole) trichloroacetyl chloride in 200 milliliters toluene was refluxed at about 110° C. for 20 hours. After removal of the low boiling material in vacuo, the resulting residue was recrystallized from benzene to give 20.0 grams (91% yield) pure product; m.p. 158° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH2:18][P:19]([OH:22])([OH:21])=[O:20])=[CH:5][C@@H:6]([NH2:17])[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[H][H]>O.[Pd]>[OH:1][CH2:2][CH2:3][C:4]([CH2:18][P:19]([OH:22])([OH:21])=[O:20])=[CH:5][C@@H:6]([NH2:17])[C:7]([OH:9])=[O:8]
Reactant: N[C@H](C=C(CCO)CP(=O)(O)O)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: N[C@H](C=C(CCO)CP(=O)(O)O)C(=O)O
Yield: 61.7 %

Procedure:
2.5 g (7.59 mmol) of benzyl 6-hydroxy-2(R)-amino-4-phosphonomethyl-hex-3-enoate are dissolved in 35 ml of water and, after addition of 0.25 g of 10% palladium on charcoal, subjected to hydrogenolysis under normal pressure. When no more hydrogen is taken up, the catalyst is filtered off over diatomeic earth, and the filtrate is hydrophilized. 1.12 g (61% yield) of 6-hydroxy-2(R)-amino-4-phosphonomethyl-hex-3-enoic acid are thus obtained. ee=91%; αD -59° (c=1.0 H2O).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:39]1[CH2:40][CH2:41][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[CH2:37][CH2:38]1
Reactant: OCc1cc2ccccc2s1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc(N2CCN(Cc3cc4ccccc4s3)CC2)nc1

Procedure:
The product from Example 8A (300 mg 1.8 mmol), methane sulfonic anhydride (313 mg, 1.8 mmol), and DIEA (200 μL 5.4 mmol) were combined. After stirring, 1-(2-pyridinyl)piperazine (328 mg, 2.9 mmol) in 4 ml DCM was also combined and the mixture was processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (d, J=8.48 Hz, 1H) 7.32 (m, 2H) 7.52 (m, 2H) 7.77 (m, 1H) 7.90 (m, 1H). (ESI) m/z 310 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([O:31][CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[CH:35][CH:34]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 531.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:5]1[C:6]2[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)=[CH:14][CH:13]=2)[N:10]=1.Cl>CO>[CH3:23][N:21]1[CH:22]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9]3[N:10]=[C:5]([N:4]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:3][CH2:2][OH:1])[C:6]4[CH2:27][NH:26][CH2:25][CH2:24][C:7]=4[N:8]=3)=[CH:17][CH:16]=2)[CH:19]=[N:20]1
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CN(C(=O)OC(C)(C)C)CC4)cc2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CNCC4)cc2)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (882 mg, 1.63 mmol) was dissolved in methanol (5 mL). Hydrochloric acid (0.136 mL, 1.63 mmol) was added and the reaction mixture was stirred at 70° C. for 1 h. The solvent was evaporated under reduced pressure and the crude was used in the next step without further purification.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>O>[OH:10][CH:11]([NH:3][C:2]1[N:4]=[C:5]([NH:6][CH:11]([OH:10])[C:12]([Cl:15])([Cl:14])[Cl:13])[N:7]=[C:8]([NH2:9])[N:1]=1)[C:12]([Cl:15])([Cl:14])[Cl:13]
Reactant: Nc1nc(N)nc(N)n1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: O
Product: Nc1nc(NC(O)C(Cl)(Cl)Cl)nc(NC(O)C(Cl)(Cl)Cl)n1
Reaction time: 3 h
Yield: 81 %

Procedure:
This compound has previously been prepared by Bump and Atkinson [J. Am Chem. Soc., 72, 629 (1950)]. Melamine (44.2 g, 0.3 mole) was added all at once to a stirred solution of chloral (221.2 g, 1.5 mole) dissolved in 375 ml. of water at 70°-80° C. The reaction mixture was stirred for 3 hours and the white precipitated product was filtered to give an 81% yield after drying. The product had a melting point >200° C. and decomposed on further heating.
Reaction SMILES: C(O)(=O)C.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]2[C:23]3[N:22]4[CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]([NH2:27])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:6]=1.[NH:28]1[C:32]2[N:33]=[CH:34][CH:35]=[C:36]([C:37](O)=[O:38])[C:31]=2[CH:30]=[CH:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]2[C:23]3[N:22]4[CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]([NH:27][C:37]([C:36]4[C:31]5[CH:30]=[CH:29][NH:28][C:32]=5[N:33]=[CH:34][CH:35]=4)=[O:38])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:6]=1
Reactant: O=C(O)c1ccnc2[nH]ccc12
Reactant: NC1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(NC1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
In a 100 ml round-bottomed flask under argon, a mixture of 116 mg of 5-quinolin-3-yl-9H-pyrrolo[1,2-a]indol-9-ylamine acetate obtained according to the preceding stage, 63 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (which can be obtained according to WO 2003/000688), 82 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 58 mg of 1-hydroxybenzotriazole (HOBt) in 7.5 ml of dimethylformamide is stirred at ambient temperature for 18 hours. The reaction medium is evaporated to dryness under vacuum, 50 ml of water are added to the residue, and the suspension is stirred for 1 hour. The solid is filtered and washed with water, then with a saturated solution of sodium bicarbonate and again with water. The resulting product is spin-filter-dried overnight and then the solid is taken up in a mixture of methanol and dichloromethane (10/90 v/v), and the solvent is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of methanol and dichloromethane (3/97 v/v). 53 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (5-quinolin-3-yl-9H-pyrrolo[1,2-a]indol-9-yl)amide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: C(OC(=O)[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([CH3:16])[C:12]=1[C:13]([OH:15])=O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:15][C:13]1[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:7]=[C:8]2[S:9][CH:10]=[C:11]([CH3:16])[C:12]=12
Reactant: CCOC(=O)C(=CNc1scc(C)c1C(=O)O)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2scc(C)c2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
In a flask equipped with a Dean-Stark trap, a mixture of 2-((3-ethoxy-2-(ethoxycarbonyl)-3-oxoprop-1-enyl)amino)-4-methylthiophene-3-carboxylic acid (Preparation 25, 4.58 g) and phenyl ether (50 mL) is degassed by freeze-pump-thaw method and then heated to reflux. After approximately 30 min, the reaction mixture is allowed to cool to room temperature. The crude mixture is purified by column chromatography (CH2Cl2; CH2Cl2/methanol, 100/1) to afford 1.95 g of the title compound as a yellow solid. Physical characteristics. M.p. 189-192° C.; 1HNMR (400 MHz, CF3CO2D) δ 11.65, 9.10, 7.31, 4.66, 2.76, 1.53; MS (ESI−) m/z 236 (M—H). Anal. Found: C, 55.66; H, 4.67; N, 5.85; S, 13.40.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C:20]1[N:21]=[C:22]([NH:25][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=2)[S:23][CH:24]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1cccc(Oc2ccnc(Cl)c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Yield: 73.9 %

Procedure:
Methyl 3-(2-chloropyridin-4-yloxy)benzoate (3.05 g, 11.6 mmol), 4-methylthiazol-2-amine (26.3 mL, 10.5 mmol), potassium phosphate (2.45 g, 11.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.241 g, 0.263 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.167 g, 0.289 mmol) were reacted in toluene (26 mL) and water (8 mL) according to Example 17, Step B to afford methyl 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoate (2.65 g, 68.7% yield) as yellow solid. 1H NMR (CDCl3) δ 8.15 (d, J=5.85 Hz, 1H), 7.89 (dt, J=1.17, 7.80 Hz, 1H), 7.70 (m, 1H), 7.45 (t, J=7.80 Hz, 1H), 7.24 (m, 1H), 6.44 (dd, J=1.95, 5.85 Hz, 1H), 6.25 (m, 2H), 3.88 (s, 3H), 2.14 (d, J=1.17 Hz, 3H). Mass spectrum (esi) m/z=342 (100) (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][OH:19])[C:9]=2[CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][C@@H:16]1[CH2:17][C@@H:15]1[C:14]1[C:9]2[CH2:8][CH2:7][O:6][C:10]=2[CH:11]=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Methane sulfonyl chloride (6.5 mmol) was added dropwise to a solution of (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methanol (5.0 mmol) and triethylamine (7.5 mmol) in 50 mL of CH2Cl2 at 0° C. The resulting mixture was allowed to warm to RT and stirred for 2 h. The crude reaction mixture was then diluted with CH2Cl2 (50 mL) and washed sequentially with water (2×50 mL), saturated aqueous sodium bicarbonate solution (2×50 mL) and then brine (1×50 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.38 g of the desired product as an oil (quantitative yield).