Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[Cl:12].C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[Cl:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[CH:21]=[O:22])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Clc1cnc2ccccc2c1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cnc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4-bromo-3-chloroquinoline (A275-2) (1.00 g, 4.12 mmol) and THF (16.5 mL) under nitrogen, and the solution was cooled to −78° C. To the cooled mixture was added n-butyllithium (2.5 M solution in hexane, 1.65 mL, 4.12 mmol) and the mixture was stirred at −78° C. for 1 hour. To the mixture was added DMF (1.60 mL, 20.6 mmol) dropwise, and the mixture was allowed to warm to room temperature. After 4 h, the mixture was quenched with saturated aqueous NH4Cl (20 mL). The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (1×50 mL). The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a brown syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 20% EtOAc in hexane, and dried under high vacuum to give 3-chloroquinoline-4-carbaldehyde (A275-3) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (1H, s), 9.10 (1H, s), 8.68-8.73 (1H, m), 8.15 (1H, dd, J=8.5, 0.9 Hz), 7.79-7.92 (2H, m); LCMS (ESI) m/z 192.1 (M+H)+.
Reaction SMILES: [ClH:1].FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OC[CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=CN2N=CN=1.[F:43][C:44]1[CH:45]=[C:46]([NH:63][C:64]([NH:66][C:67](=[O:76])[CH2:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=2)=[S:65])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:62])[C:58]([O:60][CH3:61])=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1>C1COCC1>[ClH:1].[F:43][C:44]1[CH:45]=[C:46]([NH:63][C:64]([NH:66][C:67](=[O:76])[CH2:68][C:69]2[CH:70]=[CH:71][C:72]([F:75])=[CH:73][CH:74]=2)=[S:65])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:62])[C:58]([O:60][CH2:61][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-morpholinoethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (30 mg, 0.072 mmol, Compound C of Example 36) in 1 mL of THF was added 2-(4-fluorophenyl)ethanoyl isothiocyanate (19 mg, 0.1 mmol, Compound A of Example 2). The solution was allowed to stir at room temperature for 2 h and HPLC analysis indicated the completion of the reaction. The reaction was then quenched with NH3 in propanol and the resulting solution was loaded on a preparative HPLC to be purified. Following a work-up procedure similar to that for Compound D of Example 36, the title compound (13 mg, 30%) was obtained as a HCl salt. 1H NMR (DMSO-d6) δ 12.45 (s, 1H), 11.85 (s, 1H), 11.50 (br s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.90 (d, 1H), 7.50 (m, 2H), 7.40 (m, 2H), 7.20 (m, 2H), 4.50 (br s, 2H), 4.00 (m, 2H), 3.85 (s, 2H), 3.25-3.70 (m, 8H), 2.40 (s, 3H); MS(ESI+) m/z 583.2 (M+H)+.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:27])=[C:23]([F:26])[CH:24]=3)[C:19](=[O:28])[C:18]([C:29]([O:31]CC)=[O:30])=[CH:17]2)[CH:15]=1)=O)(C)(C)C>>[NH2:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:27])=[C:23]([F:26])[CH:24]=3)[C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17]2)[CH:15]=1
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2cc(F)c(C)cc2c1=O
Agent: Cl
Product: Cc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2cc1F
Reaction time: 4 h
Yield: 85.5 %

Procedure:
12N Hydrochloric acid (5 ml) was added to ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-7-fluoro-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (400 mg), and the mixture was stirred for 4 hours while heating under reflux. After the reaction mixture was allowed to cool, solids deposited were collected by filtration, washed successively with water and ethanol and dried to obtain the title compound (250 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.C(N(C(C)C)CC)(C)C.[Br:25][C:26]1[CH:27]=[N:28][C:29](Cl)=[N:30][CH:31]=1.O>C(#N)C>[Br:25][C:26]1[CH:27]=[N:28][C:29]([N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[CH2:7]2)=[N:30][CH:31]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 76.8 %

Procedure:
Add to a solution of (2,4-dichlorobenzyl)-(S)-pyrrolidin-3-ylamine (300 g, 1.22 mol) in acetonitrile (2.25 L) at room temperature diisopropylethylamine (237 g, 1.83 mol) and 5-bromo-2-chloropyrimidine (237 g, 1.23 mol). Reflux for 1 hour. Cool the mixture to 20° C. Add water (45 mL, 2.5 mol) dropwise to give a solid. Stir for 17 h., filter the suspension, and wash the cake with acetonitrile (250 mL), and dry under vacuum at room temperature to give the title compound as a tan solid (377 g, 83%).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15].O>CS(C)=O>[N+:14]([C:5]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=1[OH:1])([O-:16])=[O:15]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Powdered sodium hydroxide (48 g) was added in portions over a period of 24 hours to a stirred solution of 4-chloro-3-nitrobenzotrifluoride (90 g) in dimethylsulfoxide (120 ml). After stirring the mixture vigorously for a further day another portion of powdered sodium hydroxide (4.8 g) was added and stirring was continued for a further 8 hours period. The mixture was poured into cold water (1 litre) and extracted with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with diethyl ether and the ethereal phase was washed with brine. The washed ethereal solution was dried over anhydrous magnesium sulfate and the solvent was evaporated to give the title compound as a brown oil (50 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCN(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min then 1.6 g (0.01 mole) of 1-phenylpiperazine was added. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml), dried and concentrated in vacuo to yield 5.1 g of crude dark yellow oil, which solidified when cooled to -78° C. Recrystallization from isopropyl ether yielded 2.2 g (54.3%) of pale yellow crystals, m.p. 93°-94° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2SC=CN=2)=[CH:4][CH2:3]1.FC(F)(F)S([O:36][C:37]1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)[CH2:45][CH:46]=1)(=O)=O>>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[O:36][CH:37]=[CH:46][CH:45]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiofuran (prepared by the addition of 53.4 mg (0.52 ml, 0.78 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (−78° C.) of 53.4 mg (0.784 mmol) of furan in 1.0 mL of THF).
Reaction SMILES: C(OC(=O)[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH:17]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[C:18]2[NH:22][C:21](=[O:23])[N:20]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:19]=2)[C:10]=1[F:39])C.[OH-].[Na+].C(O)(=O)C>O>[F:39][C:10]1[C:9]([O:8][CH2:7][CH2:6][OH:5])=[CH:14][C:13]([O:15][CH3:16])=[CH:12][C:11]=1[CH:17]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)[C:18]1[NH:22][C:21](=[O:23])[N:20]([C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:29]=2)[N:19]=1
Reactant: CCOC(=O)OCCOc1cc(OC)cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
After the atmosphere in the reaction vessel had been replaced with nitrogen, the suspension containing carbonic acid 2-{3-[(4-cyanophenylamino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester ethyl ester obtained in Example 65 was added at a bath temperature of 15° C., and rinsing in with methanol (2407 mL) and tetrahydrofuran (826 mL). 5 N aqueous sodium hydroxide solution (1599 mL, 7.995 mol) was added dropwise to the mixture at the bath temperature of 15° C., then the bath temperature was set at 20° C., and the reaction suspension was stirred for 16 hours. Thereafter, the bath temperature was set at 15° C., and acetic acid (2288 mL) was added dropwise to the solution obtained. Then, the bath temperature was set at 22° C., and water (3750 mL) was added dropwise. Seed crystals of the captioned compound (374 mg, 0.836 mmol) were added to the mixture which was then stirred for 20 minutes. Then, water (3754 mL) was added dropwise, and the bath temperature was cooled to 0° C. over a period of about 2 hours. Stirring was maintained for 16 hours at the bath temperature of 0° C. The precipitate was filtered, washed with water (2250 mL), and dried under reduced pressure at 40 to 50° C. to obtain the captioned compound (660 g, net weight 631.6 g) as a pale yellow white powder.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:31])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:29][CH3:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:29][CH3:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccc(OC)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (300 mg, 1.54 mmol), 2-amino-5-methoxy-indan-2-carboxylic acid ethyl ester (435 mg, 1.85 mmol), HATU (878 g, 2.31 mmol) in anhydrous DMF (10 mL) is added DIPEA (382 μL, 2.31 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (92) as a pale yellow oil (569 mg, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[NH:18][C:17]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[N:45]([C:46]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:44]=[N:43][N:42]=2)=[CH:31][CH:30]=1)=[N+]=[N-]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[N:18]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[N:45]([C:46]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=5)[C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[N:44]=[N:43][N:42]=4)=[CH:33][CH:34]=3)[C:17]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nn(-c2ccc(OCc3ccccc3)cc2)c(=O)[nH]1
Product: CCCCc1nn(-c2ccc(OCc3ccccc3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 81 %

Procedure:
The alkylation of 2-[4-(benzyloxy)phenyl]-5-n-butyl-2.4-dihydro-3H-1,2,4-triazol-3-one with 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole (see Example 2, Step B) was carried out as described in Example 4, Step D. After work-up, flash chromatography over silica gel using 0.4-0.5% MeOH/CH2Cl2 gave an 81% yield of the product, homogeneous by TLC in 1% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 800 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.O>ClCCl>[CH2:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-aminododecane (5.67 g, 30 mmol), methanesulfonyl chloride (2.52 ml, 32.6 mmol) and triethylamine (4.5 ml, 32.6 mmol) in dichloromethane (30 ml) was stirred at room temperature for 14 hours. The mixture was poured into water and the layers were separated. Evaporation of the dried (magnesium sulfate) organic layer gave a solid, which after trituration with cold hexane gave the title sulfonamide. 1HNMR(CDCl3): 0.92 (t, 3H, J=7.1 Hz), 1.29 (br s, 18H), 1.60 (2H), 2.99 (s, 3H), 3.16 (dd, 2H, J=13.3 Hz, 6.4 Hz) and 4.25 (br, 1H). HRMS exact mass calculated for C13H30NO2 (M+H)+ 264.1997, found 264.1993.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M252) (0.22 g, 0.38 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (150 mg, 86%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:24]([C:23]([O:30][CH3:31])=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=Cc1ccc(OCCOc2ccc3ncccc3c2)cc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 4-[2-(6-quinolinoxy)ethoxy]benzaldehyde (1.25 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution was concentrated under a vacuum to give title compound (1.51 g, 87%).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5](O)[N:4]=1.O.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][C:5]1[N:4]=[C:3]([CH:2]([F:10])[F:1])[CH:8]=[CH:7][N:6]=1
Reactant: Oc1nccc(C(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: FC(F)c1ccnc(Cl)n1
Temperature: 85 °C

Procedure:
4-(difluoromethyl)pyrimidin-2-ol was diluted with phosphorus oxychloride (80 mL) then heated at 85° C. for 3 hours with periodic venting of the reaction mixture. The mixture was cooled to rt, diluted with DCM (500 mL) and poured into water (˜1 L) cooled in an ice bath at such a rate the exotherm was maintained at ˜30° C. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2×500 mL) and the organics were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-4-(difluoromethyl) as a light yellow oil. MS ESI calcd. for C5H4ClF2N2 [M+H]+ 165. found 165. 1H NMR δ ppm DMSO-d6): 8.18 (1H, d, J=6.25 Hz), 6.63 (1H, t, J=54.22 Hz). 6.57 (2H, d, J=6.26 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:34]([O:36][C:37](=[O:40])[C:38]#[N:39])[CH3:35].Cl[Sn](Cl)(Cl)Cl>O=P(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]2[N:39]=[C:38]([C:37]([O:36][CH2:34][CH3:35])=[O:40])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C#N
Reactant: O=C(Nc1ccccc1)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)nc2ccccc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide (14 g, 39.28 mmol, 1.00 equiv), POCl3 (140 mL) and PCl5 (8.96 g, 43.03 mmol, 1.10 equiv). The resulting solution was stirred for 2 h at 65° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted with chlorobenzene (300 mL). To this was added 2-ethoxy-2-oxoacetonitrile (7.7 mL, 2.00 equiv), tetrachlorostannane (15 mL, 1.50 equiv). The resulting solution was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at 120° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether:tetrahydrofuran (30:6:1). This resulted in 4 g (23%) of ethyl 2-[4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phenyl]quinazoline-4-carboxylate as a light yellow solid. MS (ESI) m/z 438 ([M+H]+).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][NH:14][CH2:13][CH2:12][C@H:4]13.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl.CCN(CC)CC>[CH:16]1([C:19]([N:14]2[CH2:13][CH2:12][C@H:4]3[N:5]4[CH2:11][CH2:10][C:7]5[CH:8]=[CH:9][CH:1]=[C:2]([C:6]4=5)[C@H:3]3[CH2:15]2)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole from Example 3 (0.050 g, 0.25 mmol) was dissolved in CH2Cl2 (5 mL) with Et3N (0.75 mL) and cooled to 0° C. The cyclopropanecarbonyl chloride (0.026 g, 0.26 mmol) was then added dropwise. The solution was stirred at 0° C. for 1 h and then warmed to room temperature and stirred for 1 h. The reaction mixture was partitioned between water and CHCl3 (3×15 mL) and the layers separated. The aqueous layer was extracted with CHCl3. The combined organics were washed with brine, H2O and dried (Na2SO4) and evaporated affording a light yellow liquid which was further purified by preparatory silica gel TLC (5% MeOH/CH2Cl2). The title compound was isolated as a clear colorless liquid (0.042 g, 65%). 1H NMR (CD3OD, 300 MHz) δ 7.22-7.58 (m, 3H), 4.62-4.75 (m, 1H), 3.85-4.30 (m, 5H), 3.55-3.62 (m, 2H), 1.9-2.18 (m, 3H), 0.75-0.9 (m, 4H) ppm.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([O:18]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[OH:6])=[N+]=[N-].[H][H].[C:28]([OH:31])(=[O:30])[CH3:29]>C(O)C.[Pd]>[C:28]([OH:31])(=[O:30])[CH3:29].[NH2:1][CH2:4][C@H:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([OH:18])=[CH:9][CH:8]=1)[OH:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: NC[C@@H](O)c1ccc(O)c2c1OCC(=O)N2
Reaction time: 18 h

Procedure:
A solution of 8-(2-azido-1-hydroxyethyl)-5-(benzyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one, Isomer 2 (example 13, step a) (0.72 g) in a mixture of acetic acid (10 mL) and ethanol (10 mL) was stirred vigorously with 10% palladium on carbon catalyst (0.225 g) under 4 bar pressure of hydrogen for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.225 g) added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.225 g) added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was triturated with acetonitrile (30 mL) to afford the subtitled compound. Yield 0.28 g.