Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]([CH3:17])([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH3:20][C:21]1[N:22]=[CH:23][O:24][C:25]=1[CH2:26][NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:16][C:8]([O:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][NH:27][CH2:26][C:25]2[O:24][CH:23]=[N:22][C:21]=2[CH3:20])=[CH:4][CH:5]=1)([CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: Cc1ncoc1CN
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ncoc1CNCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.25 g (4.73 mmol) of tert-butyl 2-(4-formylphenoxy)-2-methylpropanoate (Example I-4) and 0.64 g (5.67 mmol) of (4-methyl-1,3-oxazol-5-yl)methylamine (Example III-28) are together initially charged in 1,2-dichloroethane. At room temperature, 1.50 g (7.09 mmol) of sodium triacetoxyborohydride are added. The reaction mixture is stirred at room temperature for 4 hours and then admixed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically on silica gel (dichloromethane/methanol 30:1) and then dried under reduced pressure. This gives 1.104 g (65% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1/[C:10]2[CH:17]=[C:16]([C:18]([O:20]C(C)(C)C)=[O:19])[S:15][C:11]=2[NH:12][C:13]/1=[O:14].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1/[C:10]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[S:15][C:11]=2[NH:12][C:13]/1=[O:14]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(=O)OC(C)(C)C)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
tert-Butyl (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (0.5 g, 1.45 mmol) was dissolved in dichloromethane (8 ml), cooled to 0° C., treated with trifluoroacetic acid (2 ml) and stirred for 3 hours warming to room temperature. The reaction mixture was evaporated to dryness and triturated with diethyl ether to give 300 mg of (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylic acid as a red solid. MS(ES): m/e 291 [M+H].
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](O)=[O:37])=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([C:34]5[CH:33]=[CH:32][C:31]6[O:27][CH2:28][O:29][C:30]=6[CH:35]=5)=[O:37])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
The title compound, off-white solid (97 mg, 82%), MS (ISP) m/z=477.3 [(M+H)+], mp 233° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and benzo[1,3]dioxole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 60 %

Procedure:
4-(3-Chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (78.3 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolid-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 75 mg (60%) of the titled compound as a yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]3)=[C:31]([O:41][CH3:42])[CH:30]=2)[N:21]=1>CO>[CH3:27][O:26][C:24]1[N:23]=[C:22]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]3)=[C:31]([O:41][CH3:42])[CH:30]=2)[N:21]=[C:20]([N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]2)[N:25]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: O=C(O)CC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N2CCC(CC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
4-Piperidineacetic acid hydrochloride (381 mg, 2.12 mmol) was suspended in 10 ml of methanol. Triethylamine (0.9 ml, 6.45 mmol) was added, followed by (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (700 mg, 2.02 mmol). The resulting mixture was stirred overnight at room temperature, concentrated and subjected to column chromatography on Si—NH2 (Isolute) using dichloromethane/methanol 95:5 v/v as an eluent. The material isolated was further purified by several triturations in water to give the final compound (792 mg, 87%) as a slightly brownish solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].P(Cl)(Cl)[Cl:16]>CC(C)=O.N1C=CC=CC=1>[Cl:16][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CC(C)=CCc1ccc(C(C)O)cc1
Reactant: ClP(Cl)Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)=CCc1ccc(C(C)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
166 g of 1-(p-prenylphenyl)ethanol was dissolved in a mixture of 870 ml of acetone and 34.5 g of pyridine. While the solution was maintained at 0° C., 60.1 of phosphorus trichloride was added over the course of about 2 hours. The mixture was stirred at room temperature for 2 hours. Acetone was distilled off, and n-hexane and cold water were added to the mixture. The n-hexane layer was washed successively with a 1.6% aqueous solution of sodium hydroxide and water, dried and concentrated to give 174.6 g of 1-chloro-1-(p-prenylphenyl)ethane.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[CH3:28][CH:27]([NH:30][C:31]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:32])[CH3:29]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)NC(C)C)c4)CC3)cccc2n1

Procedure:
The title compound was prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 30 mg), isopropyl isocyanate (10.2 μL) using toluene (1 mL) as solvent according to Method E. Yield 23 mg.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([CH2:20][C:21](=O)[CH2:22][CH3:23])[C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[O-]CC.[Na+].O>C(O)C>[CH2:22]([C:21]1[CH2:20][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:26])([F:25])[F:1])[CH:4]=2)[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:23]
Reactant: CCC(=O)CN(C(=O)Cc1cccc(F)c1)c1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC1=C(c2cccc(F)c2)C(=O)N(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
2.74 g (7.47 mmol) of N-(3-trifluoromethylphenyl)-N-(2-oxobutyl)-3-fluorophenylacetamide synthesized in the same manner as in Example 3 were dissolved in 30 ml of ethanol, and 0.05 ml of an ethanol solution containing 30% of sodium ethoxide was added thereto at room temperature with stirring. The solution was stirred at the same temperature for 2 hours, and the resultant reaction mixture was then poured into water, followed by extraction with ethyl acetate. Afterward, the resultant organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration, and then washed with diethyl ether to obtain 2.15 g of the desired product in the state of colorless crystals (yield 82.4%).
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[C:3]1[C:27]#[N:28].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:2]1[C:3]([C:27]#[N:28])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccccc2)[nH]c1=O
Product: N#Cc1c(Cl)nc(-c2ccccc2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of crude 6-oxo-4-(4-phenoxyphenyl)-2-phenyl-1,6-dihydropyrimidine-5-carbonitrile and phosphorus oxychloride (4 mL) was stirred at 90° C. for 1 h, concentrated, dissolved in dichloromethane (10 mL) and water (20 mL) and carefully neutralized with solid potassium carbonate until CO2 bubbling stopped. The mixture was extracted with dichloromethane (3×5 mL). The combined extracts were dried (MgSO4) and concentrated to give crude 4-chloro-6-(4-phenoxyphenyl)-2-phenylpyrimidine-5-carbonitrile as tan solid. The crude material was taken to next reaction without purification. MS (ES+) m/z: 384 (M+H); LC retention time: 5.190 min (analytical HPLC Method 13 except with 2 min hold at 100% B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[S:21][CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:24]=4)=[O:19])[CH:16]=3)[NH:11][C:10](=[O:31])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([OH:19])[C:20]4[S:21][CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:24]=4)[CH:16]=3)[NH:11][C:10](=[O:31])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(=O)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(O)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A mixture of intermediate (18) (0.0336 mol) in methanol (100 ml) and THF (100 ml) was cooled on an ice bath. Sodium tetrahydroborate (0.0336 mol) was added portionwise. The mixture was stirred at a low temperature for 30 min, then poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was crystallized from 2-propanone/DIPE. The precipitate was filtered off and dried, yielding 14.2 g (81.6%) of ethyl 4-(3-chlorophenyl)-1,2-dihydro-6-[hydroxy(4-phenyl-2-thiazolyl)methyl]-2-oxo-3-quinolinecarboxylate (intermediate 19), mp. 127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1)C(=O)OC
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 12 h
Yield: 84 %

Procedure:
Dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)methylene)malonate (424 mg, 1.2 mmol) was dissolved in 10 mL dry THF and 1.0M phenylmagnesium bromide in THF (5 mL, 5.0 mmol) was added. The reaction mixture was stirred for 12 h. The reaction was quenched with MeOH then poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC and eluting with 1:3 EtOAc/hexane. Obtained 435 mg (84% yield) of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)malonate. MS found: (M+H)+=333.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[CH:11][CH:12]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(O)cc3)ccnc2n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(OS(=O)(=O)C(C)C)cc3)ccnc2n1

Procedure:
The product from Example 165d (43 mg, 0.085 mmol) was reacted with isopropylsulfonyl chloride (14.5 mg, 0.102 mmol), N,N-diisopropylethylamine (33 mg, 0.255 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (16 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.38 (d, J=6.99 Hz, 6H) 2.73 (s, 3H) 3.54-3.65 (m, 1H) 6.69 (d, J=6.99 Hz, 1H) 7.01 (d, J=9.19 Hz, 2H) 7.20 (d, J=9.19 Hz, 2H) 7.27 (d, J=8.82 Hz, 1H) 7.60 (dd, J=8.82, 2.57 Hz, 1H) 7.70-7.75 (m, 2H) 8.51 (d, J=6.99 Hz, 1H) 8.81 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 484 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH2:14])[CH:10]=[C:11]([NH2:13])[CH:12]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[NH2:14][C:9]1[CH:10]=[C:11]([NH:13][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])[CH:12]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(N)cc(N2CCOCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1cc(NC(=O)C2CC2)cc(N2CCOCC2)c1

Procedure:
A solution of 5-morpholinobenzene-1,3-diamine (0.074 g, 0.383 mmol), triethylamine (0.080 mL, 0.574 mmol), cyclopropanecarbonyl chloride (0.035 mL, 0.383 mmol), and DCM (2 mL) was stirred at 23° C. for 3 h, then concd. The concentrate was partitioned between EtOAc and water, and the products were extracted twice with 25% 2-propanol in chloroform. The combined organics were dried over magnesium sulfate and concd, affording N-(3-amino-5-morpholinophenyl)cyclopropanecarboxamide as a brown amorphous solid. Mass Spectrum (ESI) m/e=262.2 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[C:6]([O:18][CH3:19])[CH:5]=1)#[N:2].[NH2:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>C(O)(=O)C>[CH3:16][N:15]([CH3:17])[C:13]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[C:1]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:2]=[C:10]2[OH:11])=[CH:5][C:6]=1[O:18][CH3:19])=[O:14]
Reactant: COc1cc(CC#N)c(C(=O)O)cc1C(=O)N(C)C
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(=O)N(C)C
Temperature: 130 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A mixture of 6-Cyanomethyl-4-methoxy-N,N-dimethyl-isophthalamic acid (2.0 g, 7.6 mmol), 3-amino-5-methylpyrazol (1.5 g, 15.44 mmol), acetic acid (10 ml) were sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 1.5 ml MeOH, and this solution was added dropwise to 30 ml water. After stirred for 1 hour, the solid was collected and was purified by flash column chromatography to give product (2.2 g, 85%). LC-MS: m/e 342 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].ClCCl.[NH3:27]>CO>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:1][C:2]([NH2:27])=[S:3])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(N)=S)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 98.1 %

Procedure:
To a stirred solution of 20 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine in 325 parts of dichloromethane were added 40 parts of methanol, saturated with ammonia. The reaction mixture was stirred for 5 days at room temperature. The precipitated product was filtered off, washed with dichloromethane and dried, yielding 20.5 parts (98.1%) of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea; mp. 265.2° C. (int. 1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].[BH4-].[Na+]>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-BOC-4-piperidone (2.00 g) and 2-methoxyethylamine (872 μl) were stirred together in methanol (20 ml) at room temperature for 12 hours. Sodium borohydride (760 mg) was added in several aliquots over 30 minutes and the reaction mixture stirred for a further 12 hours at ambient temperature. The solvents were removed in vacuo and the residue diluted with dichloromethane (50 ml) and washed with brine, dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by flash silica chromatography to give 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.69 g) as a colourless oil. To a solution of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (425 mg) stirring in anhydrous acetonitrile (10 ml) was added benzyl bromide (215 μl), followed by potassium carbonate (340 mg) and the reaction mixture heated to reflux for 12 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH:30][C:19]([C:18]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)=[O:20])[CH2:25][O:24]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3[nH]ncc3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.5 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (150 mg, 0.38 mmol) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (83 mg, 0.57 mmol) in DMF (4 mL) was added EDCI (80 mg, 0.42 mmol), HOBt (56 mg, 0.42 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 3.5 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (135 mg, 68%). LCMS (Method B): RT=3.45 min, [M+H]+=527.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([C:9]2[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)c1csc(C2CCCC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2CCCC2)n1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.67 g) was added to solution of ethyl 2-cyclopentylthiazole-4-carboxylate (example 59, step c) (0.9 g) in a mixture of THF (40 mL) and water (10 mL). The resulting mixture was stirred overnight. The reaction was acidified with aqueous HCl solution (2M, 10 mL) and the solvent evaporated. The residue was partitioned between brine (50 mL) and ethyl acetate (50 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a pale yellow solid. Yield 0.77 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26]>N1C=CC=CC=1>[CH2:30]=[CH:29][CH2:28][O:27][C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
A mixture of 4.0 gm (12.6 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 2.7 mL (25.2 mMol) allyl chloroformate in 200 mL pyridine was heated at 50° C. for 5 hours. At this point an additional 2 mL of allyl chloroformate were added and heating was continued for another 1.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue partitioned between 1N sodium hydroxide and chloroform. The phases were separated and the aqueous phase was extracted well with chloroform. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. This residue was dissolved in 2M ammonia in methanol for two hours. The reaction mixture was concentrated under reduced pressure and the residue subjected to flash silica gel chromatography, eluting with dichloromethane containing from 2-5% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 2.9 gm (60%) 5-(N-[prop-1-en-3-yloxycarbonyl]amino)-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine.