Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6-hydroxyhexyl)carbamate (12.18 g, 56.05 mmol) and TEA (8.51 g, 84.08 mmol) in 100 ml of methylene chloride, methanesulfonyl chloride (9.63 g, 84.08 mmol) was slowly added at 0° C. The mixture was stirred at room temperature overnight. The compound was purified by silica chromatography using heptane/ethyl acetate as eluent.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:19][C:20](OCC)=[O:21])[CH:15]=[CH:16][CH:17]=1.C(Cl)Cl>CCCCCC>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:19][CH:20]=[O:21])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(c1cccc(Br)c1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)c4cccc(Br)c4)c3)ncnc21
Reaction time: 4 h
Yield: 76 %

Procedure:
Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a −78° C. solution of ethyl 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirring for 4 h, the reaction was quenched with cold methanol (300 μL), and then saturated ammonium chloride (500 μL) was added and the resulting solution was stirred for 1 h. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with hexane:EtOAc, (2:1 to 1:2), to give 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (400 mg, 70%) as an oil. 1H NMR (400 MHz, CDCl3): δ 9.9 (s, 1H), 8.9 (s, 1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.4 (m, 2H), 6.8 (d, 1H), 6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01 (s, 9H). m/z=526, 528 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:37][CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:37][CH2:38][C:39](=[O:40])[NH:41][CH:42]([CH3:44])[CH3:43])=[O:9]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)NC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
To a solution of 5-fluoro-2-nitrobenzoic acid (370 mg, 2.0 mmol) in anhydrous DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (330 mg, 2.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) and 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (230 mg, 2.0 mmol). The resultant mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, the crude yellow residue dissolved in EtOAc (20 mL) and washed with dilute HCl (aq.) (3×5 mL), sat. NaHCO3 (aq.) (3×5 mL) and brine (1×5 mL). The organic layer was dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica gel with MeOH:DCM (1:19, v/v) as eluent to afford 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (INTERMEDIATE IV.1) (400 mg, 1.4 mmol, 70%) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)=[CH:6][CH:5]=[C:4]([O:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[N:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Br:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:11]=2)=[CH:6][CH:5]=[C:4]([O:18][CH:19]([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])[N:3]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(OC(C(F)(F)F)C(F)(F)F)nc2Br)c1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cccc(C(=O)Nc2ccc(OC(C(F)(F)F)C(F)(F)F)nc2Br)c1)c1ccccc1

Procedure:
Using N-[2 bromo-6-(2,2,2-trifluoro-1-trifluoromethylethoxy)-pyridin-3-yl]3-aminobenzamide and benzoyl chloride, the desired title product was prepared according to the conditions as described in Example 1-4 (Yield: 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](Cl)[C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1cc(Cl)c(C)nc1Oc1c(C)cc(C)cc1C
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC

Procedure:
A mixture of 4 chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (500 mg, 1.56 mmol) and 1-ethyl-propyl-amine (0.8 ml) in 1 ml of DMSO was heated at reflux for 15 hours. The mixture was quenched with sat. ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 445.6 mg of yellow solid. The solid was purified through silica gel column chromatography using 1:1 ratio of chloroform:hexane as eluent to give (289 mg, 50%)of the title compound as white crystals, mp 98-102° C.; 1H NMR (CDCl3) δ 8.04 (d, 1H), 6.85 (s, 2H), 6.06 (s, 1H), 3.85 (s, 3H), 3.32 (m, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.62 (m, 4H), 0.95 (t, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[Cl:21][CH2:22][C:23](OCC)(OCC)OCC.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[Cl:21][CH2:22][C:23]1[NH:8][C:7]2[CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:4]=[C:3]([C:19]#[N:20])[C:2]=2[N:1]=1
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1N
Reactant: CCOC(CCl)(OCC)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc2[nH]c(CCl)nc12

Procedure:
To a solution of 3,4-diamino-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (1.6 g) and 2-chloro-1,1,1-triethoxyethane (3.41 g,) in acetonitrile (40 ml) was added ytterbium triflate (180 mg, 5 mol %) and the mixture heated to reflux over-night. The mixture was concentrated under reduced pressure before partitioning between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over sodium sulfate and concentrated before addition of diethylether (20 ml). The precipitate was filtered and dried under a stream of air to afford the title compound. 1H NMR (MeOD) δ 8.40 (s, 1H) 8.32-8.38 (m, 2H) 8.13-8.15 (d, 2H) 7.68-7.78 (m, 2H) 4.96 (s, 2H). MS m/z 337.5, 339.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>CN(C)C=O>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2c1
Yield: 48.8 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide (230 mg, 0.50 mmol) produced in Example A21(iv), 2-chloro-2-oxoethyl acetate (273 mg, 2.00 mmol) and N,N-dimethylformamide (5 mL), and in the same manner as in Example A19, the title compound (126 mg, 49%) was obtained as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:24])[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[S:14][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:25]1CCOCC1.C(#N)C.O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:24])[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[S:14][C:13]=3[C:12](=[O:25])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: OC1(c2ccc(Cl)cc2)CCCCc2sc(-c3ccncc3)cc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C1CCCC(O)(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-4-ol (46.3 mg, 0.130 mmol) in 1,4-dioxane (3.0 mL, 38.0 mmol), acetonitrile (3.0 mL, 57 mmol) and water (2 mL, 100 mmol) were added copper(II) sulfate pentahydrate (145.0 mg, 0.580 mmol) and potassium persulfate (180.0 mg, 0.666 mmol). The reaction mixture was stirred for 16 hr at 90° C. during which time a yellow-greenish suspension was obtained and the blue color of the reaction disappeared.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[F:32][C:27]1[CH:26]=[C:25]([CH:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:44]5[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:42][CH2:43]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[F:31]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(F)c(F)c2)C3)cc1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccc(F)c(F)c3)C4)cc2)CC1

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(3,4-difluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and 1-(2-methoxyethyl)piperazine instead of piperidine to afford 6-(3,4-difluorophenyl)-N-(4-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine. M.p.=267-270° C. 1H NMR 400 MHz (DMSO-d6) δ 11.13 (s, 1H), 9.68 (s, 1H), 8.34 (s, 1H), 8.29 (d, J=6.8 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.55-7.44 (m, 2H), 7.37-7.20 (m, 4H), 7.08 (d, J=5.2 Hz, 1H), 6.92-6.85 (br, 1H), 4.43 (t, J=6.4 Hz, 1H), 3.90-3.10 (m, 17H), 3.19-3.12 (m, 2H), 3.08-3.00 (m, 2H). LCMS m/e 557 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:19]([OH:21])=[O:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:20][C:19]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][C:15]([O:18][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:19][C:9]1[CH:10]=[CH:11][CH:12]=[CH:17][CH:8]=1)=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc2ccc(O)cc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2ccc(OCc3ccccc3)cc2c1OCc1ccccc1

Procedure:
K2CO3 (2.88 g, 20.0 mmol), dry DMF (6.4 mL), 1,7-Dihydroxy-naphthalene-2-carboxylic acid (0.635 g, 3.11 mmol), and benzyl chloride (1.72 mL). Yield: 0.805 g of golden brown viscous product (55%, 2 steps).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O.S(O)(O)(=O)=O.O[NH:76][C:77]([NH2:79])=[NH:78].ONC(N)=N>CN(C=O)C>[NH2:79][C:77]1[N:78]=[C:24]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:76]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: N=C(N)NO
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1ccc(C2CC(c3nc(N)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, a solution of 2.50 g (6.31 mmol) of the carboxylic acid from Example 21A in 50 ml of DMF was admixed at RT with 3.94 g (7.57 mmol) of PYBOP and 2.20 ml (12.6 mmol) of N,N′-diisopropylethylamine. Subsequently, the mixture was stirred at RT for 30 min and then the solution was added dropwise within 1.5 h to a suspension of 5.04 g (18.9 mmol) of hydroxyguanidine hemisulphate hemihydrate, 3.30 ml (18.9 mmol) of N,N′-diisopropylethylamine and 4 Å molecular sieve. The reaction mixture was stirred at RT for 1 h and then filtered through a frit. The residue was washed with 50 ml of DMF and then the combined organic phases were stirred at 130° C. (preheated oil bath) for 40 min. Subsequently, the solvent was removed under reduced pressure and the residue was admixed with 30 ml of diethyl ether and 30 ml of 1 N aqueous sodium hydroxide solution, and stirred vigorously for 24 h. The organic phase was removed and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 3.00 g (77% of theory, purity 65%)
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([CH3:26])[CH2:25][CH2:24][C:19]4([C:21]([F:23])([F:22])[CH2:20]4)[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[N:39]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40]1>ClCCl.CN(C)C1C=CN=CC=1>[N:39]1([S:43]([NH:46][C:9](=[O:10])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([O:14][CH2:15][C:16]3([CH3:26])[CH2:17][CH2:18][C:19]4([C:21]([F:22])([F:23])[CH2:20]4)[CH2:24][CH2:25]3)=[CH:6][C:7]=2[F:13])(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CCC2(CC1)CC2(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
To a stirred solution of 5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]-octan-6-yl)methoxy)-2-fluorobenzoic acid (0.039 g, 0.106 mmol) in dichloromethane (3 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (0.031 g, 0.159 mmol) and 4-dimethylaminopyridine (0.030 g, 0.244 mmol). The reaction was stirred at ambient temperature for 10 minutes, azetidine-1-sulfonamide (0.023 g, 0.17 mmol) was added and the stirring was continued at ambient temperature for 17 hours. The reaction was concentrated, diluted with ethyl acetate (10 mL) and washed with 5% aqueous hydrochloric acid solution (5 mL). The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 30% ethyl acetate in hexanes) afforded the title compound (0.043 g, 83%) as a white solid [mixture of cis/trans diastereomers]: 1H NMR (300 MHz, CDCl3) [second diastereomer peaks in italics] δ 8.64 (d, J=16.5 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 6.58 [6.56](d, J=14.0 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.77 [3.72](s, 2H), 2.32-2.19 (m, 2H), 2.06-1.94 (m, 1H), 1.82-1.37 (m, 6H), 1.29-1.10 (m, 5H), 1.08-0.83 (m, 4H), 0.70-0.60 (m, 2H); MS (ES−) m/z 485.3 (M−1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:13]2)[CH2:11][CH2:10]1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>C1COCC1>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]([OH:32])[C:15]2[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:13][N:12]([CH:9]3[CH2:10][CH2:11]3)[C:16]=2[C:17]([F:18])([F:19])[F:20])=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(C(F)(F)F)n(C2CC2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
LDA (3.70 mL, 6.66 mmol) was added dropwise to a stirred solution of ethyl 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.1) (1.18 g, 4.75 mmol) in THF (30 mL). After 15 minutes at −78° C., a solution of 4-chlorobenzaldehyde (668 mg, 4.75 mmol) in THF (5 mL) was slowly added. The reaction was stirred at −78° C. for 15 min, quenched with 1 mL of saturated NH4Cl solution, partitioned between EtOAc and water and both phases separated. The aq. phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel column chromatography (hexane/20% EtOAc) to afford the title product (1.5 g, 3.40 mmol, 71% yield) as a yellow solid. tR: 1.27 min (LC-MS 2); ESI-MS: 389 [M+H]+ (LC-MS 2); Rf=0.22 (hexane/EtOAc 8:2).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH3:15][N:16]([CH3:19])[C:17]#[N:18]>>[CH3:15][N:16]([CH3:19])[C:17]([NH2:18])=[N:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CN(C)C#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: Cl
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Temperature: 10 °C

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (2.1 g) and N,N-dimethylcyanamide (7 ml) was heated under nitrogen at 165°-170° C. for 12 hours. The reaction mixture was cooled to 10° C. and the precipitate collected by filtration, washed with ether and stirred with 40% aqueous sodium hydroxide solution. The resulting mixture was extracted with dichloromethane and the extract washed with brine and dried. Removal of the solvent yielded a residue which was recrystallised from hexane to give 1,1-dimethyl-2 (2-morpholinophenyl)guanidine (m.p. 144°-145° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(Cl)ccc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,5-dichloroaniline to yield 2-[(2,5-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:23][N:24]1[CH2:28][CH2:27][CH:26](O)[CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH:26]3[CH2:27][CH2:28][N:24]([CH3:23])[CH2:25]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CN1CCC(O)C1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2, 639 mg, 2.0 mmol) in DCM (30 ml) was added 1-methyl-3-pyrrolidinol (658 μl, 6.0 mmol) and triphenyl phosphine (1572 mg, 6.0 mmol). The suspension was cooled to 0° C. under a nitrogen atmosphere. Di-tent-butyl azodicarboxylate (1380 mg, 6 mmol) was added as a solution in DCM (20 ml), dropwise over the course of 15 minutes. The resulting light brown solution was allowed to warm to room temperature and was stirred overnight. The solution was evaporated, and the residue purified by chromatography, eluting with 0 to 5% methanol in DCM. The appropriate fractions were combined and evaporated, and the crude product (230 mg) re-dissolved in 1:1 methanol/DCM (5 ml). Ethereal HO (1M, 1.14 ml) was added, and the mixture evaporated. Crystallisation from ethanol diethyl ether gave the title product as a hydrochloride salt in the form of a white crystalline solid (154 mg, 16%); 1H NMR (hydrochloride salt): 2.30 (m, 1H), 2.65-2.75 (m, 1H), 2.88 (s, 3H), 3.30-3.80 (m, 3H), 3.85-4.05 (m, 1H), 4.00 (s, 3H), 5.46 (m, 1H), 7.35 (dd, 1H), 7.45 (s, 1H), 7.51 (dd, 1H), 7.62 (dd, 1H), 8.53 (s, 1H), 8.72 (s, 1H), 8.81 (s, 1H); Mass Spectrum: 403.3, 405.3.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1.Br[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[Cl-].[NH4+]>CN(C)C=O>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[CH2:17][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1
Reactant: BrCc1nc2ccccc2o1
Reactant: COC(=O)Nc1ccc(O)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3o2)cc1C
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
52.8 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 200 mg of methyl N-(4-hydroxy-2-methylphenyl)carbamate [prepared as described in Example 15(a) above] in 5 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 5 minutes, and then 305.4 mg of 2-bromomethylbenzoxazole [prepared as described in step (a) above] were added. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 20 minutes. At the end of this time, the temperature of the reaction mixture was elevated to 50° C. and the mixture was stirred for a further 1 hour. A saturated aqueous ammonium chloride solution was then added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 320.4 mg (yield 85.5%) of the title compound as a solid having a melting point of 159° to 162° C.