Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:39])=[C:5]([C:30]([O:37]C)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:34][O:33][C:32]1[C:3](=[O:2])[C:4]([CH3:39])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:30](=[O:37])[C:31]=1[O:35][CH3:36]
Reactant: COc1c(C)c(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 61.9 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(tert-butoxycarbonylmethyloxy)benzoyl]morpholine (0.290 g, 0.533 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.731 g, 1.33 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.170 g, 0.330 mmol, 62%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[C:1]1([S:7][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To the solution of thiophenol (0.5 g, 0.463 mL, 4.5 mmol) in DMF (6 mL) was added potassium carbonate (0.94 g, 6.8 mmol) and the mixture was stirred at room temperature for 15 minutes. 4-fluoro benzaldehyde (0.675 g, 0.574 mL, 5.4 mmol) was added and the reaction mixture stirred at 80° C. for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture quenched with water (20 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (25 mL×2) then with brine (25 mL), dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain title compound (0.94 g, 96%).
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[C:20]([F:29])[C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([CH:30]2[CH2:32][CH2:31]2)[CH:17]=1)=[O:15])C.C(N(CC)CC)C>N1C=CC=CC=1>[CH:30]1([N:18]2[C:19]3[C:24](=[CH:23][C:22]([F:27])=[C:21]([N:8]4[CH2:9][CH2:10][C:6]5([O:5][CH2:4][CH2:3][CH2:2][O:1]5)[CH2:7]4)[C:20]=3[F:29])[C:25](=[O:26])[C:16]([C:14]([OH:15])=[O:13])=[CH:17]2)[CH2:31][CH2:32]1
Reactant: C1COC2(CCNC2)OC1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC4(C3)OCCCO4)c(F)cc2c1=O

Procedure:
A 0.276 g (1.8 mmol) sample of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2 Example 14, 0.400 g (1.29 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (preparation described by K. Grohe, et al., DE 3318145, November 1984) and 0.52 mL (3.7 mmol) of triethylamine and 12 mL of pyridine were heated at 65° C. for 48 hours in dry glassware and under dry nitrogen. The solvent was evaporated and the ester purified by chromatography on a silica gel column using as eluant 0.5% methanol in methylene chloride increasing to 2% methanol in methylene chloride. The solvent was removed to afford 0.218 g of the title compound, which was taken to the next step directly.
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][C:8]([CH3:15])=[CH:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:3]#[CH:4]>C1C=CC=CC=1.[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:12](=[CH:11][CH2:10][CH2:9][C:8]([CH3:15])=[CH:7][CH2:6][CH2:5][C:2]([CH3:1])([OH:16])[CH:3]=[CH:4][C:4]#[C:3][C:2]([CH3:1])([OH:16])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:13]
Reactant: C#CC(C)(O)CCCC(C)=CCC=C(C)C
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)(O)C#CC=CC(C)(O)CCC=C(C)CCC=C(C)C
Yield: 94 %

Procedure:
In contact with triphenylphosphine rhodium chloride [RhCl (PPh3)3 ] catalyst, 3,7,11-trimethyl-7,10-dodecadien-1-yn-3-ol was refluxed in benzene for 3 hours. The reaction mixture was concentrated and purified by column chromatography (developer system: benzene-chloroform =1:1). Analysis of the product by gel permeation chromatography showed that the starting material had substantially reacted to yield 2,6,10,15,19,23-hexamethyl-2,6,11,18,22-tetracosapentaen-13-yn-10,15-diol (94% selectivity). The resulting acetylenic diol was hydrogenated in n-hexane and in contact with 5% palladium-on-carbon at room temperature and elevated pressure of 80-100 kg/cm2 to yield 2,6,10,15,19,23-hexamethyltetracosa-10,15-diol (bp. 218-220° C. / 0.2 mm Hg). This product was subjected to hydrogenolysis in acetic acid in contact with palladium-on-carbon at a hydrogen pressure of 100 kg/cm2 and at a reaction temperature of 170-190° C. The resultant compound was analyzed by gas chromatography and nuclear magnetic resonance spectroscopy and the data comformed with a standard sample of squalane.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:31]4[CH:30]=[C:29]5[C:34](=[CH:33][CH:32]=4)[NH:26][CH:27]=[CH:28]5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5[nH]ccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-5-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:8]2=[N:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[CH3:17][C@@:18]([C:23]([NH2:25])=[O:24])([CH:20]([CH3:22])[CH3:21])[NH2:19]>>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[N:9][C:8]([C:12](=[O:13])[NH:19][C:18]([C:23](=[O:24])[NH2:25])([CH3:17])[CH:20]([CH3:22])[CH3:21])=[C:7]([CH:6]=1)[C:15]([OH:14])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(C)[C@](C)(N)C(N)=O
Reactant: CC(=O)Oc1cc2c(nc1C)C(=O)OC2=O
Product: CC(=O)Oc1cc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)nc1C

Procedure:
6.3 g (28.48 mmol) 5-acetoxy-6-methyl-pyridine-2,3-dicarboxylic acid anhydride and 4.1 g (31.33 mmol) 2-methyl-valinamide are stirred under nitrogen for 2 days at room temperature, and then the precipitated crystalline product is filtered off.
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.[N:33]([C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)=[C:34]=[O:35]>ClCCl>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([NH:33][C:34]([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:35])[CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[O:44][CH3:45]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

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, 0.20 mmol) (Aldrich), followed by the addition of 5-isocyanato-1,2,3-trimethoxy-benzene (33 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. 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 (3,4,5-trimethoxy-phenyl)-amide (Yield 35 mg, 44.9%).
Reaction SMILES: [C:1]([CH2:5][C:6]([OH:8])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:52][CH2:53][C:54]1[O:58][C:57]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[C:70]([CH3:71])=[CH:69][CH:68]=[C:67]([C:72]([NH:74][CH:75]4[CH2:77][CH2:76]4)=[O:73])[CH:66]=3)=[CH:61][CH:60]=2)=[N:56][N:55]=1>CN(C=O)C>[CH:75]1([NH:74][C:72]([C:67]2[CH:66]=[C:65]([C:62]3[CH:63]=[CH:64][C:59]([C:57]4[O:58][C:54]([CH2:53][NH:52][C:6](=[O:8])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:55][N:56]=4)=[CH:60][CH:61]=3)[C:70]([CH3:71])=[CH:69][CH:68]=2)=[O:73])[CH2:77][CH2:76]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: CC(C)(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)CC(C)(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-Butylacetic acid (10 mg) and HATU (33 mg) in DMF (1 ml) were stirred for 10 minutes at room temperature. To this solution was added HOBt (11.6 mg), DIPEA (0.45 ml) and 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in DMF (3 ml) and the reaction stirred at room temperature for 72 hours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2×5 ml). The organic phase was reduced to dryness and the residue purified by bond-elut (silica, 5 g) eluting with an ethyl acetate/cyclohexane gradient and then by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4′-(5-{[(3,3-dimethylbutanoyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:27]C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH2:23][CH3:27])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CCI
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2cn(C)nc2C)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 0.698 mmol) in DMF (5 ml) cooled with an ice-bath was added 55% NaH in oil (1.398 mmol). The RM was stirred for 30 min at rt then was added iodoethane (0.085 ml) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc and washed with saturated aqueous NaHCO3, with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (CH2Cl2/MeOH 0% to 3.5%). The fractions containing product were evaporated together to give the title compound as a brown solid. (HPLC: tR 2.41 min (Method A); M+H=386, 388 MS-ES)
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([O:7]CC)=O.[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:43]>C(O)C.O1CCOCC1>[ClH:43].[Br:16][C:14]1[CH:15]=[C:10]([C:4]2[C:5](=[O:7])[N:18]([C:20]3[CH:21]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:24][N:25]=3)[NH:2][CH:3]=2)[CH:11]=[N:12][CH:13]=1
Reactant: NNc1cc(N2CCOCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 100° C., 500 mg (1.7 mmol) of the compound from Example 11A, 326 mg (1.7 mmol) of the compound from Example 9A and 58 mg (0.3 mmol) of p-toluenesulfonic acid are stirred in 4 ml of ethanol for 16 h. After cooling to RT, 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added, and the mixture is stirred at RT for 30 min. The precipitate is filtered off, washed first with ethanol and then with diethyl ether and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:35][C:34]1[C:25]([NH:24][C:22]2[C:21]([Cl:36])=[CH:20][N:19]=[C:18]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)[N:23]=2)=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH:29][CH3:30])=[O:28]
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
3-Chloro-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidine-4-ylamino}-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-chloro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (25 mg, 14%). LCMS (m/e) 515 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.82 (s, 1H), 7.58 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.7 Hz), 7.31-7.25 (m, 1H), 7.10 (s, 1H), 6.99 (d, 1H, J=8.0 Hz), 6.96 (s, 1H), 6.86 (d, 1H, J=8.0 Hz), 6.03-5.93 (m, 1H), 3.56-3.52 (m, 2H), 3.37 (s, 3H), 2.88-2.82 (m, 2H), 2.76-2.60 (m, 12H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cccc(-c2csc(Br)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Yield: 69.3 %

Procedure:
A solution of 2-bromo-4-(3-fluorophenyl)-1,3-thiazole (800 mg, 3.10 mmol), tert-butyl piperazine-1-carboxylate (1.15 g, 6.20 mmol) and potassium carbonate (428 mg, 3.10 mmol) in dimethylformamide (10 ml) was stirred at 120° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 781 mg (69.4%) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42]O>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[N:13]([CH2:42][C:38]3[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cn1ccnc1CO
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NC(=O)N2c1ccccc1Cl
Product: Cn1ccnc1CN1C(=O)N(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=614.1 (M+H+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 1-methylimidazole-2-methanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:30](O)[CH3:31]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:14]([O:16][CH2:30][CH3:31])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(Nc2cccc(C)c2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 1-benzyl-4-(3-methylphenylamino)piperidine-4-carboxylic acid (3.81 g, 11.7 mmol) and concentrated sulfuric acid (2 mL) in absolute ethanol (80 mL) was heated under reflux overnight. The resultant solution was concentrated under vacuum, and the residue was treated with chloroform saturated with ammonia gas. The mixture was filtered, and the filtrate concentrated. The residue was passed through a small plug of silica gel eluting with chloroform saturated with ammonia gas. Collection and concentration of the eluent under vacuum provided the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[O:20]>O1CCCC1>[C:1]([CH:3]([CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[O:20])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: Cc1ccccc1C(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C#N)CC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
2′-Methylacetophenone (16.0 g) was dissolved in chloroform (50 mL) and diethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform (15 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) as an oil. To a solution (700 mL) of methyl cyanoacetate (10.9 g) and diisopropylethylamine (31.0 g) in tetrahydrofuran was added dropwise a solution (100 mL) of crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) obtained above in tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hr, then at 70° C. for 2 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate as an oil (yield 16.0 g). This was dissolved in ethyl acetate (16 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate as an oil (yield 2.7 g). This was dissolved in methanol (15 mL), 10% palladium carbon (50% containing water, 1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.66 g, 3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]#[C-:9].NCCCCCC[OH:17].C(OC)=O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]=[O:17]
Reactant: [C-]#[N+]CCCCCCO
Reactant: NCCCCCCO
Solvent: COC=O
Product: O=CNCCCCCCO

Procedure:
The 6-hydroxyhexyl isocyanide used in the preparation of the isocyano copolymer was synthesized as follows: To 214.4 g (2 moles) of 6-aminohexyl alcohol, which was stirred and heated to keep the material molten, was added dropwise 120.1 g (2 moles) of methyl formate. When the addition was completed, the mixture was stirred and heated at reflux for two hours. After removal of the methanol formed in vacuo, the residue was recrystallized from tetrahydrofuran to give 237.4 g of 6-hydroxyhexylformamide, m.p. 43.5°-45°.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)[CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
A solution of acryloyl chloride (20 μL, 0.25 mmol) was added dropwise to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 150, 180 mg, 0.42 mmol) and triethylamine (73 lilt, 0.53 mmol) in THF (3 mL) at −5° C. over a period of 1 minute under an atmosphere of N2. The resulting mixture was stirred at 0° C. for 0.25 h. The reaction was judged to be incomplete so further acryloyl chloride (10 μL, 0.125 mmol) was added dropwise and the mixture was stirred at 0° C. for a further 15 minutes. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH2Cl2 (5 mL) plus a few drops of CH3OH. This solution was washed with sat. NaHCO3 (2 mL), dried (MgSO4) and filtered through a 1 g silica pad, eluting with 4:1 CH2Cl2—CH3OH. Eluent that contained desired product was concentrated in vacuo. Purification by FCC, eluting with 5-20% CH3OH in CH2Cl2 gave the title compound (31 mg, 14%) as a cream crystalline solid; 1H NMR: 2.33 (3H, s), 2.40 (2H, s), 2.57 (2H, d), 3.03 (2H, s), 3.89 (3H, s), 5.70 (2H, m), 6.17 (1H, m), 6.46 (1H, m), 6.88 (1H, s), 7.09 (1H, t), 7.32 (1H, d), 7.47 (1H, t), 8.12 (1H, s), 8.21 (1H, s), 8.39 (1H, d), 8.51 (1H, d), 8.81 (2H, m), 9.36 (1H, s); m/z: ES+ MH+ 482.