Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[Cl:12][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1cc(N2CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
To a solution of 2,6-dichloropyrimidine-4-carboxylic acid methyl ester (300 mg, 1.45 mmol) in dimethylsulfoxide (2 ml) is added morpholine (0.126 g, 1.0 eq) followed by diisopropylethylamine (0.285 ml, 1.1 eq). The mixture is stirred at room temperature for 15 h before being diluted with water and extracted with ethyl acetate (2×20 ml). The combined organic layers are washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel, eluted with ethyl acetate:hexane (1:1) to provide methyl 2-chloro-6-morpholin-4-ylpyrimidine-4-carboxylate as a white solid (0.30 g). Mp: 135-138° C., 1H NMR (300 MHz, DMSO-d6) δ 7.34 (s, 1H), 3.86 (s, 3H), 3.67 (brs, 8H). MS: 257 (M+1).
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:15]([F:17])[F:16].[C:27]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([CH:14]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]([F:17])[F:16])=[C:7]([CH:12]=1)[CH2:6][NH:5][C:36](=[O:37])[C@@H:35]1[CH2:39][CH2:40][CH2:41][N:34]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN)C(F)F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Yield: 50.9 %

Procedure:
EDC (0.171 g, 1.25 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.314 g, 0.96 mmol), N-BOC-L-proline (0.207 g, 0.96 mmol) and HOAT (0.171, 1.25 mmol) in DMF (2.0 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic layer was washed with 1M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and reduced in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-50% ethyl acetate/hexanes gradient) to give N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (0.256 g) as a foam; LC-MS m/z=524.3.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:20])[C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.Cl.Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1OC1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=CN=1>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][O:14][C:12]1[C:11]([CH3:20])=[C:10]2[N:9]([CH:13]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:4][C:3]1[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:2]=1[F:1]
Reactant: Cc1c(OCCN(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN(C)C)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 96.5 %

Procedure:
2-(4-(2-Fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-N,N-dimethylethanamine (22 mg, 0.06 mmol) was converted to the title compound (20 mg, 100%) in a manner similar to the preparation of Compound B of Example 28. The resultant yellow glass was used in the next step without further purification. MS(ESI+) m/z 346.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(Cl)=[O:38].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:37]([NH:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:38])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.207 g, 0.54 mmol) in CH2Cl2 (2 mL) at 0° C. was added diisopropylethylamine (0.21 mL, 1.19 mmol), followed by phosgene (20% in toluene; 0.34 mL, 0.65 mmol), and the reaction was stirred for 2 hours at 0° C. Benzylamine (0.09 mL, 0.81 mmol) was then added, and the reaction was stirred for 15 minutes. Triethylamine (0.1 mL, 0.72 mmol) was added, and the reaction was stirred for 1 hour. Additional benzylamine (0.09 mL, 0.81 mmol) and diisopropylethylamine (0.21 mL, 1.19 mmol) were added, and the reaction was stirred for 3 hours, until no starting material was seen by analytical LCMS. The mixture was partitioned between H2O and CH2Cl2, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].C1COCC1.B.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C#N)cc1Br
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CN)cc1Br
Temperature: 50 °C

Procedure:
3-Bromo-4-(methyloxy)benzonitrile (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux. The additional 1.5 M borane in THF (30 mL, 45 mmols) and reflux continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. The reaction was worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. This mixture was then heated to 50° C. for 4 h. The solvents were pumped off, and the residue partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound. LC-MS m/z 198.7 (M−NH2), 0.99 min (ret time).
Reaction SMILES: [Cl:1][CH:2]([Cl:35])[C:3]([NH:5][C@H:6]([CH2:33][F:34])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3C(OC(C)(C)C)=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][CH:2]([Cl:1])[C:3]([NH:5][C@H:6]([CH2:33][F:34])[C@H:7]([OH:8])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3CCCN3)cc2)cc1)C(Cl)Cl
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of the product of step 1 (210 mg, 0.4 mmol) in DCM (3 mL) is added TFA (1 mL). The mixture is stirred for 1 hour. The reaction is then diluted with DCM, washed with sat.NaHCO3 (aq.) and evaporated to give the title compound (144 mg). 1H-NMR (400 MHz, DMSO) δ(ppm) 1.5-1.65 (1H), 1.7-1.9 (2H), 2.1-2.25 (1H), 2.8-3.0 (1H), 3.0-3.2 (1H), 4.05-4.15 (1H), 4.15-4.35 (1.5H), 4.35-4.45 (0.5H), 4.5-4.6 (0.5H), 4.65-4.75 (0.5H), 4.8-4.9 (1H), 5.9-6.0 (1H), 6.5 (1H), 7.4-7.5 (4H), 7.5-7.65 (4H), 8.6 (1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])=[N+:2]=[N-:3].Br[C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16].C(O)(C)(C)C>O>[F:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][N:1]1[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Br)C(=O)OC
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
In a preferred embodiment 2-(azidomethyl)-1,3- difluorobenzene is treated with methyl 2-bromoacrylate in mixture of t-butanol and water to produce methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]([OH:16])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][C:37]([C:43]#[N:44])=[C:36]2[NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Br:52])[CH:47]=1.C([O-])(O)=O.[Na+]>C1COCC1.N1C=CC=CC=1>[Br:52][C:48]1[CH:47]=[C:46]([NH:45][C:36]2[C:35]3[C:40](=[CH:41][CH:42]=[C:33]([NH:32][C:14](=[O:16])[C:13]#[C:12][CH2:11][N:8]4[CH2:7][CH2:6][C:5]5([O:1][CH2:2][CH2:3][O:4]5)[CH2:10][CH2:9]4)[CH:34]=3)[N:39]=[CH:38][C:37]=2[C:43]#[N:44])[CH:51]=[CH:50][CH:49]=1
Reactant: O=C(O)C#CCN1CCC2(CC1)OCCO2
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCC4(CC3)OCCO4)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To an ice cold solution of 1.75 g (7.78 mmol) of 4-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)but-2-ynoic acid in 100 mL of THF under N2 was added 0.942 g (9.33 mmol) of N-methylmorpholine followed by 0.852 g (6.22 mmol) of isobutyl chloroformate. After stirring in the cold for 30 min, a solution of 1.05 g (3.11 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile in 8 mL of pyridine was added dropwise. After stirring in the cold for 5 h, the reaction was poured into ice water and satd NaHCO3 was added. The mixture was extracted with ethyl acetate and the extracts were dried and evaporated. Chromatography of the residue on silica gel (20% methanol in ethyl acetate) gave 0.590 g of 4-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)but-2-ynoic acid[4-(3-bromophenylamino)-3-cyanoquinol-6-yl]amide as a brown foam: mass spectrum (electrospray, m/e): M+H 546.0, 548.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=1)[C:9](=[O:22])[CH2:8][CH2:7][C:6]2([CH3:24])[CH3:23])#[CH:2].[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]#[C:1][C:3]2[CH:12]=[C:11]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:10]3[C:9](=[O:22])[CH2:8][CH2:7][C:6]([CH3:24])([CH3:23])[C:5]=3[CH:4]=2)=[CH:33][CH:34]=1
Reactant: C#Cc1cc(OCOCC[Si](C)(C)C)c2c(c1)C(C)(C)CCC2=O
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(OCOCC[Si](C)(C)C)c3c(c2)C(C)(C)CCC3=O)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-4,4-dimethyl-8-(2-trimethylsilanyl-ethoxymethoxy)-3,4-dihydro-2H-naphthalen-1-one (Intermediate 73, 1.28 g, 3.7 mmol), 4-iodo phenyl acetic acid methyl ester (1.02 g, 3.7 mmol), triethyl amine (30 mL), copper(I)iodide (0.095 g, 0.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.35 g, 0.5 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (1.61 g, 88%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1.[Cl-].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH:12]([N:10]1[CH:11]=[C:7]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:8]=[N:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)n1cc(Br)cn1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
n-Butyllithium (2.5M in hexanes, 1.38 mL, 3.45 mmol) was added over 15 min to a solution of 4-bromo-1-isopropyl-1H-pyrazole (500 mg, 2.65 mmol) in diethyl ether (10 mL) at −78° C. After 30 min, a solution of tri-n-butylstannane chloride (920 μL, 3.45 mmol) in diethyl ether (1 mL) was added and the resultant reaction mixture was left to stir at −78° C. for 1 h, then allowed to warm to ambient temperature. The reaction mixture was diluted with diethyl ether (40 mL) and washed with water (20 mL), then brine (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford the title product as a colourless oil (98 mg, 94%) which was used without further purification. 1H NMR (CDCl3, 400 MHz): 7.46-7.42 (m, 1 H); 7.28 (t, J=4.2 Hz, 1 H); 4.59-4.43 (m, 1 H); 1.58-1.42 (m, 12 H); 1.39-1.24 (m, 6 H); 1.02-0.77 (m, 15 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[C:7]1=[O:17].Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[C:7]1=[O:17]
Reactant: CN(C)CCCl
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3cccc(OCCN(C)C)c3C2=O)c(OC)c1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
A mixture of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-isoindole-1,3-dione (317 mg, 1.01 mmol), 2-dimethylaminoethyl chloride hydrochloride (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (4 mL) was heated at 60° C. for 18 hours. The mixture was concentrated in vacuo, taken up in ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous extracts were made basic with solid potassium carbonate and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give the title compound (236 mg, 61%) as an off-white solid. 1H NMR (methanol-d4) 7.73 (1H, t), 7.44-7.40 (2H, m), 7.02 (1H, d), 6.51 (1H, d), 6.42 (1H, dd), 4.72 (2H, s), 4.33 (2H, t), 3.80 (3H, s), 3.76 (3H, s), 2.87 (2H, t), 2.40 (6H, s). MS: [M+H]+ 385.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])([OH:3])=O.[NH4+].O[N:36]1C(=O)CCC1=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:36][C:1]([CH2:4][N:5]([C:10]1[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[S:6]([CH3:9])(=[O:8])=[O:7])=[O:3]
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CC(N)=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, N-hydroxysuccinimide-ammonium salt, TBTU and triethylamine in DMF.
Reaction SMILES: [CH:1]1([CH2:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:11]>>[Br:11][CH2:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCC1
Reactant: BrC(Br)(Br)Br
Product: BrCC1CCCCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 9 from cycloheptylmethanol and carbon tetrabromide. The crude product was purified by fractional distillation, b.pt. 115° C.-120° C. @ 30mmHg to afford 1-(bromomethyl)cycloheptane as an oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CO.C(Cl)Cl>[CH3:25][N:10]([CH2:9][CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: Oc1ccc(C2CCC(NCCOc3ccccc3)CC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(CCOc1ccccc1)C1CCC(c2ccc(O)cc2)CC1
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a stirred solution of 4-[4-(2-phenoxyethylamino)cyclohexyl]phenol (0.35 g, 1.13 mmol) in a mixture of MeOH (10 mL), water (1 mL) and CH2Cl2 (5 mL) was added p-formaldehyde (0.17 g, 5.62 mmol). The reaction mixture was stirred for 2 hours, sodium triacetoxyborohydride (0.33 g, 1.58 mmol) was added and stirring was continued overnight. Solid NaOH was added, until the solution turned clear. Silica gel was added, and the solvents were removed under reduced pressure. Purification by flash chromatography (10:1 CH3Cl:MeOH) gave 4-{4-[methyl(2-phenoxyethyl)amino]cyclohexyl}-phenol (264 mg, 72%) as a white solid: mp 216-220° C.; IR (KBr): 3149, 2936, 1599 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (br s, 1H), 7.34 (dd, J=9, 9 Hz, 2H), 7.00 (d, J=9 Hz, 5H), 6.68 (d, J=9 Hz, 2H), 4.42 (br s, 2H), 3.61-3.33 (m, 3H), 2.82 (s, 3H), 2.92 (t, J=5 Hz, 2H), 2.49 (tt, J10, 2 Hz, 1H), 2.19 (dd, J=10, 2 Hz), 1.88 (br d, J=10 Hz, 2H), 1.74 (dddd, J=10, 10, 10, 2 Hz, 2H), 1.47 (dddd, J=10, 10, 10, 2 Hz, 2H); CI-MS (methane) (m/z): 326 [M+H]+; HPLC: method A, 5.64 min (95.3%); method B, 9.63 min (99.2%); Anal. Calcd for C24H33NO.HCl: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.44; H, 7.81; N, 3.80.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH:33]([CH3:38])[C:34]([OH:37])([CH3:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:39])[C:18]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[C:48]([C:53]#[N:54])=[CH:49][CH:50]=[CH:51][CH:52]=2)=[CH:43][CH:42]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH:33]([CH3:38])[C:34]([OH:37])([CH3:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:39])[C:18]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[NH:3][C:4](=[O:7])[O:5][N:54]=2)=[CH:43][CH:42]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.58 g), sodium hydrogen carbonate (0.93 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({7-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.32 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.2 g, 56%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[S:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[S:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=NCCCc1ccccc1
Reactant: Nc1nccs1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCCc1ccccc1)Nc1nccs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.5 %

Procedure:
A solution of 3-phenylpropyl isothiocyanate (500 mg, 2.82 mmol) and 2-aminothiazole (300 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) was heated to 100° C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with 1N hydrochloric acid, water (3×), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 129 mg of the title product. A second crop was recrystallized from 1:1 ethyl acetate/hexanes to provide another 110 mg of the title product. Total yield of the title product: 239 mg (30%) as an off-white solid. A sample was recrystallized again from ethyl acetate:
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)[Cl:8].[CH3:11][C:12]1([CH3:18])[CH2:16][CH2:15][C:14](=O)[CH2:13]1.C([O-])(=O)C.[Na+]>ClCCl>[Cl:8][C:14]1[CH2:13][C:12]([CH3:18])([CH3:11])[CH2:16][C:15]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: CC1(C)CCC(=O)C1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(Cl)=C(C=O)C1
Temperature: 20 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of DMF (18.3 g, 250 mmol) in dichloromethane (300 mL) cooled at 0° C. was added POCl3 (40.5 g, 250 mmol) over a period of 10 minutes. See FIG. 15. The mixture was stirred at 20° C. for 1 h. To the above mixture was added 131a (28.0 g, 250 mmol) dropwise over a period of 20 minutes. The resulting mixture was heated at reflux for 20 h. The reaction mixture was cooled to room temperature and poured into a solution of sodium acetate (60 g) in ice-water (400 g). The mixture was extracted with dichloromethane (2×300 mL). The combined organic layer was washed with water (2×200 mL), dried over anhydrous Mg2SO4 and filtered. The filtrate was evaporated under reduced pressure to afford 131b as a colorless oil (33.0 g, crude). 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 2.62 (d, J=2.0 Hz, 2H), 2.38 (d, J=2.0 Hz, 2H), 1.15 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[B-](F)(F)(F)[F:10].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:10][C:2]1([CH3:1])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1C(=O)CCC1=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC1(F)C(=O)CCC1=O
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A mixture of 2-methylcyclopentane-1,3-dione (4.50 g, 40.1 mmol) and Selectfluor (17.06 g, 48.2 mmol) in acetonitrile (80 mL) was heated to reflux for 2 h, cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate, water, brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography, eluting with 20 to 50% ethyl acetate in hexanes, gave 2-fluoro-2-methylcyclopentane-1,3-dione (4.50 g, 82% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 2.65-3.19 (4H, m), 1.38-1.77 (3H, m).