Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][CH2:28][O:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C>>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([O:29][CH2:28][CH2:27][N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:31][CH:32]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Solvent: CC(=O)O
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(OCCN4CCCC4)cc3)n2)cn1

Procedure:
A mixture of 3-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopentylpropanenitrile (prepared according to the procedure described in Example 33, Step 2; 0.030 g, 0.000099 mol) and 4-(2-pyrrolidin-1-ylethoxy)aniline (0.0308 g, 0.000149 mol) in acetic acid (0.7 mL, 0.01 mol) was refluxed overnight. After being evaporated to dryness, the residue was diluted with EtOAc, washed with aqueous sodium bicarbonate, brine, dried, and concentrated. The residue was applied on RP-HPLC to obtain the desired product as a racemic mixture (free base). LCMS (M+H) 472.4.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:42])[N:12]([CH:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:21]=3[CH3:22])[CH3:16])[CH2:13][CH2:14][C:3]=12>C(O)(=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:42])[N:12]([CH:15]([C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[CH3:16])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)N(C(C)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1C(C)N1CCc2c(C)c3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 3,4-dihydro-5-methyl-2-[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a]indol-1(2H)-one (60 mg) in 70% acetic acid in water (2.6 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was dissolved in 10% methanol in chloroform. The mixture was washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (10% methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a]-indol-1(2H)-one as a powder. The powder was dissolved in 9N hydrogen chloride in ethanol (1 ml) and evaporated in vacuo. The residue was triturated with ether to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a[indol-1(2H)-one hydrochloride (36.8 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl>>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:16]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: C1COCCN1
Agent: Cl
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 0 °C

Procedure:
20.1 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 87 ml morpholine. The temperature of the thick mixture rose to 75° C. After being stirred at reflux temperature for five hours, the mixture was poured into ice water, made acidic with concentrated HCl, filtered, dried and recrystallized from ethanol to give 20.3 grams 2-morpholino-5-nitrobenzoic acid. m.p. = 168°-170° C. The nitro compound was reduced catalytically in ethanol-water (3:1) with 5% palladium on carbon catalyst to give 5-amino-2-morpholinobenzoic acid. m.p. = 307°-308° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.[Cl-].[Na+].O.[Fe]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)CC2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of Example 129A (19.68 g, 111 mmol) in ethanol (111 mL) was treated sequentially with iron powder (43.0 g, 770 mmol) and solid ammonium chloride (3.70 g, 69.2 mmol). The resulting suspension was stirred at 90° C. for 1 hour, cooled to room temperature, diluted with brine, and extracted with diethyl ether (4×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to provide the desired product as a 6:1 mixture of 6-amino- and 4-amino-1-indanone (14.20 g, 87%). 1H NMR (300 MHz, DMSO-d6, 6-amino-1-indanone) δ 7.21 (d, 1H), 6.92 (dd, 1H), 6.75 (d, 1H), 5.27 (br s, 2H), 2.90 (t, 2H), 2.54 (m, 2H); 1H NMR (300 MHz, DMSO-d6), 4-amino-1-indanone) δ 7.10 (t, 1H), 6.81 (m, 2H), 2.80 (m, 2H), 2.59 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=2)[CH:2]=1.[NH2:16][C@@H:17]([CH3:33])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=2)=[N:20]1>CN(C)C=O>[Cl:32][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:10]3[N:11]=[CH:12][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)=[O:15])[CH3:33])[N:20]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: O=C(O)c1ccc(-c2cccnc2)cn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccc(-c2cccnc2)cn1
Yield: 45.2 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(pyridin-3-yl)picolinic acid (130 mg, 0.549 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (150 mg, 0.577 mmol) using N,N-dimethyl formamide as the solvent. The product was purified by flash chromatography. Yield 45.2%. 1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 4.38 (dd, 1H), 4.46 (dd, 1H), 4.49-4.59 (m, 1H), 6.96 (d, 1H), 7.59 (q, 1H), 7.87 (d, 1H), 7.97 (dd, 1H), 8.01 (d, 1H), 8.06-8.12 (m, 2H), 8.21-8.26 (m, 1H), 8.35 (dd, 1H), 8.69 (dd, 1H), 9.01-9.07 (m, 2H), 9.14 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC1=C(c2ccc(F)cc2)CNC1=O
Product: CC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O

Procedure:
In a manner similar to that described in Preparation 8, 4-(4-fluorophenyl)-1,5-dihydro-3-methyl-2H-pyrrol-2-one is reacted with nitric acid to provide the title compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1cccc(O)c1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2cccc(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (28.83 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 37% (45 mg, 0.089 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([S:11]CC2C=CC(OC)=CC=2)=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:3]=1[F:29].[C:30](O)(C(F)(F)F)=O.C(O)=O.C(C(O)=O)CCCC>CC(O)=O>[NH2:1][C:2]1[C:10]([SH:11])=[CH:9][C:5]([C:6]([O:8][CH3:30])=[O:7])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:3]=1[F:29]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CSc2cc(C(=O)[O-])c(Nc3ccccc3F)c(F)c2N)cc1
Solvent: O=CO
Solvent: CC(=O)O
Solvent: CCCCCC(=O)O
Product: COC(=O)c1cc(S)c(N)c(F)c1Nc1ccccc1F

Procedure:
4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be deprotected in the presence of acid (such as CF3COOH, HCOOH, CH3COOH and n-C5H11COOH, prefer CF3COOH) at certain temperature (20-75° C., prefer 25-75° C.) in appropriate aromatic aliphatic ether (such as anisole and phenetole, prefer anisole) for some time (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate is obtained after conventional workup.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:27]1[CH:32]=[N:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1.CO>O1CCCC1>[CH:33]1([C:30]2[N:31]=[CH:32][C:27]([O:1][C@@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]4[CH2:3]3)=[N:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
tert-Butyl (8S,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (55 mg, 0.203 mmol, Part F) was dissolved in tetrahydrofuran (1.2 mL). Potassium tert-butoxide (0.400 mL, 0.400 mmol, 1.0 M in tetrahydrofuran, 2.0 equivalents) was added at room temperature, and the resulting solution was stirred for five minutes. Then 2-bromo-5-cyclopropylpyrazine (81 mg, 0.407 mmol, 2.0 equivalents) was added as a solution in tetrahydrofuran (0.5 mL). The reaction was allowed to stir at room temperature for 16 hours, at which point it was quenched with 3 drops of saturated sodium bicarbonate. The mixture was concentrated in vacuo, and the residue was loaded onto a 12 g silica column eluted with 100:0 to 95:5 dichloromethane:methanol over 20 minutes to give the titled compound (41 mg, 52% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.02 (d, J=1.0 Hz, 1H), 7.93 (d, J=1.4 Hz, 1H), 5.44 (t, J=4.0 Hz, 1H), 4.45-4.17 (br s, 2H), 4.07-3.98 (m, 2H), 3.67 (dd, J=13.8, 4.1 Hz, 1H), 3.00 (br s, 1H), 2.73-2.66 (m, 3H), 2.49 (dd, J=12.0, 7.6 Hz, 1H), 2.01-1.82 (m, 2H), 1.48 (s, 9H), 1.02-0.89 (m, 4H); MS (ESI+) m/z 333.0 (M-tBu+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[CH3:31][CH2:32][Mg+].[Br-].[Cl-].[NH4+]>C1COCC1.ClCCl>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]([OH:28])[CH2:31][CH3:32])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(O)c1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cn1CC
Temperature: -15 °C
Yield: 46 %

Procedure:
A mixture of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.10 g; 0.25 mmol) in THF (5 mL; anhydrous) was stirred and cooled to −15° C. To this was added an excess of EtMgBr (3.1 eq; 0.25 mL of 3.0 M solution in hexane), dropwise. The mixture was stirred at −15° C. for one hour. The reaction was worked up by carefully adding 1.0 mL of saturated aqueous ammonium chloride solution, diluting with dichloromethane (30 mL) and washing with water. The organic phase was dried over MgSO4, filtered and evaporated. Two products were separated from the crude mixture by chromatography on silica gel. The column was eluted with a chloroform/methanol mixture on a gradient (9:1 through 7:3). The more polar product was isolated and crystallized from ethyl acetate/hexane to give the title product as white crystals, 0.05 g (46% yield), mp 115-121° C.; MS (ES) m/z 434.2; [M−H]−
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:31][C:32](N(C)C)=[O:33].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:32](=[O:33])[CH3:31])[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: CC(=O)N(C)C
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reaction time: 0.17 h
Yield: 27 %

Procedure:
A 2.5 M solution (1.5 ml) of n-butyllithium in hexane was added dropwise at −78° C. into a solution (30 ml) of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (1.0 g) in tetrahydrofuran over 5 min. After 10 min, dimethylacetamide (0.34 ml) was added thereto and the resultant mixture was warmed to room temperature. Next, a saturated aqueous solution of ammonium chloride and ethyl acetate were added thereto to and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (250 mg) as a yellow powder (yield: 27%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[C:17]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[CH:4]([CH:7]=[CH:24][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH:2]1[OH:1]
Reactant: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCC(O)C1CCCCCCCO
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1CCC(O)C1CCCCCCCO
Yield: 61.6 %

Procedure:
A mixture of 3-hydroxy-2-(7-hydroxyheptyl)cyclopentanecarbaldehyde (4.5 g., 0.02 mole) and hexanoylmethylene triphenylphosphorane (7.5 g., 0.02 mole) in dry tetrahydrofuran (100 ml.) was heated under reflux for 6 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel. Elution with a 3:2 mixture of petrol (b.p. 40°-60°C.) and ethyl acetate gave 2-(7-hydroxyheptyl)-3-(3-oxo-1-octenyl)cyclopentanol (4 g., 63%), λmax 230 mμ, ε 12,900 (ethanol), νmax 1660 cm-1, 1620 cm-1 (liquid film).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][OH:27])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][O:27][S:37]([CH3:36])(=[O:39])=[O:38])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(CO)OC3=O)cc2F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 375 mg (0.95 mmol) of oxazolidinone 9 and 144 mg (0.20 mL, 1.42 mmol) triethylamine in 3.8 mL dichloromethane at 0° C. was treated dropwise with 130 mg (0.09 mL, 1.14 mmol) of methanesulfonyl chloride followed by stirring at 0° C. for 1 hour. The solution was diluted with 30 mL dichloromethane and was extracted with water (2×25 mL) and with saturated NaHCO3 (25 mL). Drying (Na2SO4) and concentration in vacuo afforded 440 mg (98%) of mesylate 10 as a white solid, sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C@@H:46]1[CH2:51][C@H:50](O)[CH2:49][CH2:48][N:47]1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:45]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][C@H:50]4[CH2:49][CH2:48][N:47]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[C@H:46]([C:44]([O:43][CH3:42])=[O:45])[CH2:51]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
DTAD (13.3 g, 57.9 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-ol (1) (4.94 g, 15.5 mmol, prepared as described in WO 03/082831, Reference Example 2 therein), triphenylphosphine (18.3 g, 69.5 mmol) and (2S,4R)—N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid methyl ester (ex ACROS, 6 g, 23.2 mmol) in DCM (150 ml) at −15° C. (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-tert-butyl 2-methyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1,2-dicarboxylate (2) (6 g, 69%) as a white foam; 1H NMR Spectrum: (DMSO d6) 1.47-1.53 (m, 11H), 1.86-1.91 (m, 1H), 2.25-2.36 (m, 1H), 2.95-3.13 (m, 1H), 3.70 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, 1H), 4.45 (m, 1H), 4.86-4.94 (m, 1H), 7.31 (t, 1H), 7.51-7.64 (m, 3H), 7.80 (s, 1H), 8.39 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 561.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH3:8])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[S:6][C:5](/[C:7](=[N:11]/[OH:12])/[CH3:8])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)c1ccc(Cl)s1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C/C(=N\O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combined 1-(5-chlorothiophen-2-yl)ethanone (100 g, 622 mmol), hydroxylamine hydrochloride (47.6 g, 685 mmol, 1.1 eq) and sodium acetate (56.2 g, 685 mmol, 1.1 eq) in 1 L of ethanol and 300 mL of water. The reaction was heated to reflux. After 3 h, the reaction was cooled to rt and concentrated. The residue was slurried in 500 mL of water overnight, filtered and dried to afford the crude solid. Purified by extraction of the solid with hot dichloromethane, cooling to rt and filtering to remove unreacted starting material. The solid was slurried in hot dichloromethane several times to extract the solid enriched in the first eluting (E-oxime) compound (100% DCM) after concentration. The highly crystalline material was purified by column chromatography using 100% dichloromethane to afford (E)-1-(5-chlorothiophen-2-yl)ethanone oxime. NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.21 (d, J=3.9 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 2.12 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]1)=[O:17]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2Cl)CC1
Yield: 83.6 %

Procedure:
In a manner similar to the procedure described in Example B except that a one liter three-necked Morton flask was used, 39.0 grams (0.14 mol) of ethyl 3-[(2,4-dichlorophenyl)amino]-3-oxopropanoate, 53.9 grams (0.39 mol) of anhydrous potassium carbonate, 125 milliliters of anhydrous dimethylformamide and 13.4 milliliters (0.16 mol) of 1,2-dibromoethane were reacted for a period of 65 hours to give 35.3 grams (0.117 mol) of ethyl 1-(2,4-dichlorophenylaminocarbonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 95.0° C.-96.0° C. The total yield was 83 percent. NMR analysis of the product indicated the following:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:10][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:5][CH:6]=[CH:7][C:8]=1I)#[N:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=1)=[O:39].C([O-])(O)=O.[Na+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[C:4]([NH:10][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:5][CH:6]=[CH:7][C:8]=1[C:44]1[CH:43]=[CH:42][C:41]([NH:40][C:38]([NH:37][C:28]2[CH:29]=[C:30]([C:33]([F:34])([F:36])[F:35])[CH:31]=[CH:32][C:27]=2[F:26])=[O:39])=[CH:46][CH:45]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N(Nc1nccc(I)c1C#N)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Nc1nccc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1C#N)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 110 mg of di-tert-butyl (3-cyano-4-iodopyrid-2-yl)-hydrazinedicarboxylate and 122 mg of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea in 5.5 mL of dioxane are added 57 mg of NaHCO3 in 1.7 mL of water. 26 mg of tetrakis(triphenylphosphine)palladium are then added and the reaction is refluxed at 100° C. After 2 hours 30 minutes, the pale yellow solution is cooled to 20° C. and 10 mL of ethyl acetate are added. The organic phase is washed twice with 8 mL of water and then with 8 mL of brine. After drying over magnesium sulfate and concentrating under reduced pressure, the residual yellow oil is purified on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (9/1 cyclohexane/ethyl acetate). 114 mg of di-tert-butyl (3-cyano-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}pyrid-2-yl)hydrazinedicarboxylate are obtained.