Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=O)[NH:6][C:5]1=[O:14])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[S:16])[NH:6][C:5]1=[O:14])[CH2:2][CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]cnc21

Procedure:
A suspension of 9.32 g. (48 mM.) of 3-propylxanthine in 80 ml. of pyridine, was treated with 17.33 g. (78 mM.) of phosphorus pentasulfide in 80 ml. of pyridine, and worked up analogously to Example I. 8.9 g. of 3-propyl-6-thioxanthine was obtained. Recrystallization from methanol-acetone gave 7.4 g. (59% yield) of needles with a melting point of 249°-250° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)(C)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C1CN(Cc2c(O)ccc3c2OCC3=O)CCN1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1CN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CCN1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazin-2-one (0.0986 g, 0.376 mmol) in isopropanol (1.5 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0550 g, 0.376 mmol) and piperidine (0.00320 g, 0.0376 mmol), and the mixture was refluxed by heating for 2 hours. The reaction mixture was cooled to room temperature, and then added with isopropanol (2 mL), and the precipitated solid was suspended in isopropanol and thereby washed. The solid was collected by filtration to obtain the objective (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazin-2-one (0.106 g, 72%).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[ClH:28].[N:31]1([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: ClCCn1ccnc1
Agent: Cl
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCn3ccnc3)cc12

Procedure:
6-(2-imidazol-1-yl-ethoxy)2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 25% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-1H-imidazole hydrochloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[C:1]([NH:4][C:5]1[CH:12]=[C:11]([Cl:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=1[C:7]#[N:8])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(Cl)ccc1C#N
Product: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1C#N
Temperature: 0 °C

Procedure:
25 g of 2-acetylamino-4-chlorobenzonitrile obtained in Step (3) above was added little by little to 200 ml of fuming nitric acid which had been cooled at 0° C. After the completion of the addition, the mixture was reacted for 30 minutes, and then the reaction solution was poured into 1 liter of ice water. The crystals thus-deposited were collected by filtration, washed thoroughly with water and dried. Yield: 22.2 g (72.4%).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15]>O1CCCC1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:17]2[N:19]=[C:20]([Cl:21])[N:13]=[C:14]([Cl:15])[N:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
Grignard reaction: In a 500 ml sulfonating flask having a stirrer, dropping funnel, condenser and internal thermometer, 7.3 g (0.3 mol) of magnesium turnings and a few grains of iodine are initially introduced into 60 ml of dry tetrahydrofuran (THF). Under dry protective gas (nitrogen), 56.1 g (0.3 mol) of 4-bromoanisole, dissolved in 100 ml of THF, are slowly added dropwise at 60° C. After the complete dissolution of the Mg turnings, the mixture is stirred at 60° C. for 90 minutes. The Grignard solution is then added dropwise at 5° C. under nitrogen in the course of 60 minutes to a solution of 55.3 g (0.3 mol) of cyanuric chloride in 150 ml of THF. The mixture is evaporated to dryness at room temperature, 500 ml of dil. hydrochloric acid are allowed to run in and the mixture is extracted with 300 ml of methylene chloride. For working-up, the solvent is removed in vacuo, and the semisolid residue is tritrated with a little isopropanol and filtered off with suction. Purification is carried out by recrystallization from toluene/hexane (1:1). 62.8 g (82% of theory) of 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine are obtained (m.p.: 131-134° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:14][CH:13]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)nc3)cc2)C1

Procedure:
6-Chloronicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 344.14 (C18H21ClN4O); MS (ESI): 345 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1>ClCCl>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])=[CH:37][CH:36]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 4-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methoxy-phenyl)-amide as a white solid. (Yield 35 mg, 50%).
Reaction SMILES: [N+:1]([C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:3])=[O:2].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[C:13]([CH2:14][Br:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Methyl 2-nitro-3-methylbenzoate (15.3 gm) was suspended in carbon tetrachloride (45 mL) along with N-bromosuccinimide (15 3 gm) and heated to reflux. 2,2'-Azobis(2-methylpropionitrile) (AIBN) (0.4 gm) was added to the refluxing solution in four equal portions over 48 hours. The reaction was cooled to room temperature, filtered, and concentrated. The residue consisted of a mixture of starting material, desired product, and dibrominated material which were difficult to separate and so were used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:23][C:24]([CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:26])[CH3:25]>>[Br:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][CH:27]([C:24]([OH:23])([CH3:26])[CH3:25])[CH2:28]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(O)C1CCNC1
Product: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine (US2010160280) and was obtained as an off-white solid. HPLC (Condition 4) tR=6.11 min, UPLC-MS (Condition 7) m/z=490.1 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]([C:20]1[CH:36]=[C:35]2[N:23]([CH2:24][C:25]3[C:26]2=[N:27][C:28]2[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=[O:37])[C:21]=1[CH2:38][OH:39])([CH2:18][CH3:19])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>ClCCl>[C:1]([O:39][CH2:38][C:21]1[C:22](=[O:37])[N:23]2[C:35](=[CH:36][C:20]=1[C:9]([OH:8])([CH2:18][CH3:19])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:26]1=[N:27][C:28]3[C:33]([CH:34]=[C:25]1[CH2:24]2)=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:3])[CH3:2]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1cc2n(c(=O)c1CO)Cc1cc3ccccc3nc1-2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(O)(CC(=O)OC(C)(C)C)c1cc2n(c(=O)c1COC(C)=O)Cc1cc3ccccc3nc1-2
Yield: 69.1 %

Procedure:
Acetic anhydride (70 μl, 0.7 mmol) is added dropwise to a solution of tert-butyl 3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate (200 mg, 0.46 mmol) and triethylamine (140 μl, 1 mmol) in dichloromethane (5 ml) and the resultant mixture is agitated at ambient temperature for 21 hours. The volatile components are evaporated off and the residue is purified by chromatography on a silica gel column (1-2% MeOH/CH2Cl2), which produces 152 mg of sought compound in the form of a yellow solid, m.p. 195-196° C.
Reaction SMILES: FC1C=[C:4](C=C(F)C=1)[CH2:5][N:6]1C=CN=C1S.[C:16]1([CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[SH:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:6][CH2:5][CH2:4][S:29][C:25]1[N:24]([CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Fc1cc(F)cc(Cn2ccnc2S)c1
Reactant: Sc1nccn1CCc1ccccc1
Product: NCCSc1nccn1CCc1ccccc1

Procedure:
The Example 1 process wherein 1-(3,5-difluorobenzyl)-2-mercaptoimidazole is replaced by 1-(phenylethyl)-2-mercaptoimidazole yields 2-(2-aminoethylthio)-1-(phenylethyl)imidazole.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][N:2]([C:8]([O:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[NH:33][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CN(CCC(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)CNC(=O)CCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of benzyl 2(S)-[N-methyl-N-(2-carboxy-ethyl)aminocarbonyloxy]-3-phenylpropionate (460 mg) and isobutylamine (143 ml) in anhydrous methylene chloride (10 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (274 mg) portionwise at 0°-5° C. After being stirred at the same temperature for 3 hours, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 0.5N hydrochloric acid (30 ml), water (30 ml), aqueous sodium bicarbonate (30 ml), water (30 ml) and brine (30 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave benzyl 2(S)-[N-methyl-N-(2-isobutylcarbamoylethyl)aminocarbonyloxy]-3-phenylpropionate (440 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].C(=O)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][C:8]2[S:9][C:10]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc(Oc2nccs2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(OC)cc2)s1
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of Example 11A (3.27 g, 15.8 mmol) in tetrahydrofuran (30 mL) was added n-butyl lithium (2.5 M in hexanes, 6.50 mL, 16.3 mmol, 1.0 eq.) at −78° C. The mixture was stirred for 1 hour. Tributyltin chloride (4.40 mL, 16.3 mmol, 1.0 eq) was then added at −78° C. (The dry ice bath was removed and the mixture was stirred for 1 hour. The reaction was quenched with water (100 mL). The aqueous layer was extracted with ether and the organic layer washed with brine, dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate: hexane gradient (0-20%) to give the title compound (7.07 g, 92%).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1CCCCC1.N1C=CC=CC=1>[C:1]([N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1=[O:20])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2=[O:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCCCCCCCCCCN1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: O=C1CCCCCCCCCCCN1C(=O)c1ccc(C(=O)N2CCCCCCCCCCCC2=O)cc1
Temperature: 0 °C

Procedure:
Terephthaloyl chloride (203 g, i mol) is added in the course of 30 minutes to a solution of ω-laurolactam (403 g, 2 mol) in 1600 ml of cyclohexane and 475 ml of pyridine at room temperature. The mixture is then refluxed for 3 h. After cooling, the flask contents are poured into 3 1 of ice water and the resulting light yellow precipitate is filtered off by suction and dried. Yield 498 g (95%).
Reaction SMILES: I[CH3:2].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[C:11]([CH3:14])[CH:12]=2)[N:7]=[C:6]([CH3:25])[CH:5]=1>CN(C)C=O>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][N:16]([CH3:2])[C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[C:11]([CH3:14])[CH:12]=2)[N:7]=[C:6]([CH3:25])[CH:5]=1
Reactant: Cc1cc(Cl)c2cc(C)c(CNc3ccc(C#N)cc3)cc2n1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2cc(C)c(CN(C)c3ccc(C#N)cc3)cc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Iodomethane (46 mg, 0.33 mmol) was added to a solution of 4-[(4-chloro-2,6-dimethyl-quinolin-7-ylmethyl)-amino]-benzonitrile (example 101b, 70 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and 1 h at r.t., then partitioned between dichloromethane and 1 M aq. sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate 2:1, then 1:1) afforded the title compound (63 mg, 86%). White solid, ISP-MS: m/e=336.2 ([M+H]+).
Reaction SMILES: [CH:1]1([C@@H:7]([OH:20])/[CH:8]=[CH:9]/[C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C>[Pd].C(Cl)Cl>[CH:1]1([C@@H:7]([OH:20])[CH2:8][CH2:9][C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](O)C3CCCCC3)[C@H](O)C[C@@H]2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](CC[C@H](O)C3CCCCC3)[C@H](O)C[C@@H]2O1
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of 43 (5.3 g, 18.9 mmol), 10% w/w Pd/C (320 mg), ethyl acetate (30 mL), and CH2Cl2 (10 mL) was hydrogenated in a Parr hydrogenation apparatus for 3 h at 45 psi. The mixture was filtered through Celite and concentrated, and the residue was chromatographed on silica gel (ethyl acetate) to afford 44 (4.3 g, 80%). 13C NMR (CDCl3) δ 177.64 (C), 83.87 (CH), 77.21 (CH), 76.02 (CH), 53.45 (CH), 43.84 (CH), 42.96 (CH), 40.46 (CH2), 35.88 (CH), 31.37 (CH2), 29.23 (CH2), 29.10 (CH2), 27.85 (CH2), 26.41 (CH), 26.22 (CH2), 26.08 (CH2).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[CH:2]1.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
tert-Butyl 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.35 g, 4.51 mmol), ammonium formate (1.42 g, 22.55 mmol) and 5% palladium on activated carbon (50 mg) in ethanol (25 mL) were stirred and refluxed for 1 hour. The resulting mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated by evaporation then treated with dilute aqueous ammonium chloride (50 mL) and extracted with DCM. The extract was washed with water, dried over MgSO4 and evaporated to a colourless solid. The solid was triturated with ether then collected by filtration and dried under vacuum to give tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate (1.088 g, 80%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[O:17])[C:13]([CH3:29])=[CH:12][C:11]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>CN1CCCC1=O>[Cl:1][C:2]1[N:6]=[CH:5][N:4]([C:10]2[N:15]=[C:14]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:20][CH2:19]3)=[O:17])[C:13]([CH3:29])=[CH:12][C:11]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)[N:3]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Clc1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-n2cnc(Cl)n2)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A well stirred solution of 0.17 g (1.59 mmol) of 3-chloro-1H-[1,2,4]triazole in 1.0 ml of 1-methyl-pyrrolidin-2-one was treated at RT with 0.058 g (1.32 mmol) of a sodium hydride (55% in mineral oil). After 30 min, 0.20 g (0.44 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was added and the reaction mixture was heated up to 150° C. After 24 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.11 g (48%) of the title compound as yellow oil. MS: 519.3 (MH+, 1Cl).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:13]=1[O:14][CH:15]1[CH2:18][N:17](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16]1>C(Cl)Cl>[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:13]=1[O:14][CH:15]1[CH2:18][N:17]([C:1]([Cl:4])=[O:2])[CH2:16]1
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(Cl)c1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
A mixture of 13.9 g (0.14 mole) of phosgene and 17.3 g (0.125 mole) of potassium carbonate in 140 mL of methylene chloride was stirred under nitrogen for 30 min then cooled in an ice water bath while 46.5 g (0.125 mole) of 3-(2-chloro-6-methylphenoxy)-1-(diphenylmethyl)azetidine in 140 mL of methylene chloride was added dropwise. After stirring for 16 h the excess phosgene was destroyed by adding small pieces of ice. Water was added to dissolve the inorganic material and the methylene chloride portion was separated, dried (filtered through Whatman PS paper) and concentrated in vacuo, 65.8 g. The oily residue was triturated with 300 mL of 30/60 pet ether and then with 300 mL of hexanes, both at ambient temperature. The remaining yellow residue was triturated with boiling hexanes and the hot solution decanted (4×200 mL). Upon cooling an orange oil separated which was removed from the hexanes solution by decanting. After decanting again, the hexanes solution was cooled in an ice bath and decanted to remove all traces of the impure orange oil. The volume of hexanes was reduced to 75 mL by heating under a stream of nitrogen. Upon cooling, crystalline product was obtained in 2 fractions (10.8 g and 5.5 g). Rework of the filtrate and the ambient temperature filtrates (300 mL of pet ether and 300 mL of hexanes) yielded an additional 6 g of product for a total yield 22.3 g crude (68.6%), mp 67°-69° . A sample was recrystallized for analysis from hexanes, mp 70°-71.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH3:37]>CN1C(=O)CCC1>[CH3:32][O:33][CH2:34][CH2:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccnc(Cl)n2)cc1
Reactant: CNCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COCCN(C)c1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Temperature: 120 °C

Procedure:
To 31.4 mg (0.10 mmol) N-(1-(4-((2-chloropyrimidin-4-yl)ethynyl)phenyl)propan-2-yl)-acetamide (170) and 25.8 μl (0.15 mmol) DIPEA in 1 mL NMP are added 26.7 mg (0.30 mmol) N-(2-methoxyethyl)methylamine. The reaction mixture is stirred in a sealed tube at 120° C. over night and purified by HPLC (MeOH/H2O/TFA).