Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)C.C(#N)C.C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][NH:38][CH:39]=[O:40])=[CH:33][CH:32]=1>>[N+:17]([C:20]1[CH:21]=[C:22]([S:26]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([NH:37][NH:38][CH:39]=[O:40])=[CH:35][CH:36]=2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=CNNc1ccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: -5 °C

Procedure:
1 1 of N,N-dimethylacetoamide, 880 g of acetonitrile, and 285 g of triethylamine were added to and dissolved in 426 g of 2-(4-aminophenyl)-1-formylhydrazine under an atmosphere of nitrogen. The solution was cooled to -5° C., and 625 g of meta-nitrobenzenesulfonyl chloride was gradually added to the solution. During the addition, the mixture was agitated under cooling so that the temperature did not exceed -5° C. The resultant mixture was cooled at a temperature below -5° C. for 1.5 hours, then the temperature thereof was raised to a room temperature. Extraction was performed with 12 l of ethyl acetate and 12 l of saturated salt water. The organic layer was separated and then concentrated to 6 l. 3 l of n-hexane was added to the concentrate, and the obtained mixture was agitated at a room temperature for 30 minutes. The produced crystals were filtered off and washed with 500 g of ethyl acetate.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:3]1.N1C(=O)C=NC=CC=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:38][C@H:39]([CH2:43][CH:44]=[CH2:45])[C:40](O)=[O:41]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[N:7]([CH2:10][C:11]([F:14])([F:12])[F:13])[C:8](=[O:9])[C@@H:2]([NH:1][C:40](=[O:41])[CH:39]([CH2:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:49])=[C:35]([Cl:34])[CH:36]=2)[CH2:43][CH:44]=[CH2:45])[N:3]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: C=CC[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: O=c1cncccn1
Product: C=CCC(Cc1ccc(Cl)c(Cl)c1)C(=O)N[C@H]1N=C(c2ccccc2F)c2ccccc2N(CC(F)(F)F)C1=O

Procedure:
Prepared from 3-amino-5-(2-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)-2-oxo-1,3-dihydro-2H-benzo[e][1,4]diazepine [available in an analogous fashion to (S)-3-amino-1-methyl-5-phenyl-1,3dihydro-2H-benzole][1,4]diazepin-2-one (i.e. J. Org. Chem. 1987, 52, 3232)] and (2S)-2-(3,4-dichlorobenzyl)-pent-4-enoic acid using the procedure of Step 1E shown in Scheme 1.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:12](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>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:12])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ncccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ncccc1C(N)=O
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 2-methylnicotinic acid (0.537 mg, 3.9 mmol) in 20 mL of DMF at 0° C. was added HATU (1.56 g, 4.1 mmol) followed by the dropwise addition of DIPEA (0.72 ml, 4.1 mmol). NH3 (g) was then bubbled into the solution for 15 mins. The reaction was allowed to stir overnight. The resulting paste was filtered and rinsed with cold DMF and discarded. The mother liquor was concentrated and purified by normal phase chromatography using CH2Cl2/7 N NH3 in MeOH: 93/7 as eluent. Yielded a white solid (405 mg, 76%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.34 (s, 9 H), 1.36 (d, J=6.64 Hz, 3H), 2.56 (s, 3 H), 4.32-4.40 (m, 1 H), 7.15-7.19 (m, J=8.20 Hz, 1 H), 7.68 (d, J=8.20 Hz, 1 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[CH3:25][NH:26][O:27][CH3:28]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:26]([O:27][CH3:28])[CH3:25])=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cncc(Br)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40 g (198 mmol) of 5-bromonicotinic acid are dissolved in 300 mL of THF and treated with 19 mL of oxalyl chloride at 0° C. 66 mL (475 mmol) of triethylamine are then added, followed by 23.2 g (237 mmol) of N,O-dimethylhydroxylamine hydrochloride. After stirring at room temperature for 4 hours, the reaction medium is poured into water and extracted with ethyl acetate. The organic phase is separated out after settling, dried over magnesium sulphate and evaporated. 45.1 g (93%) of the expected product are collected in the form of a light brown oil.
Reaction SMILES: C([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH2:14][CH3:15])[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[N:10]=1)[C:6]([OH:16])=[O:5])[CH3:15]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)O)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-ethyl-6-methyl-isonicotinic acid tert-butyl ester in DCM (10 mL) is treated with TFA (10 mL) and the mixture stirred at rt for 0.5 h. The mixture is evaporated and the residue dried under HV to give 2-ethyl-6-methyl-isonicotinic acid; LC-MS: tR=0.28 min, [M+1]+=166.25.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:15])[C:11](Br)([CH3:13])[CH3:12])[CH3:8].[F:16][C:17]1[CH:18]=[C:19]([OH:26])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:15])[C:11]([O:26][C:19]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=1)([CH3:13])[CH3:12])[CH3:8]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
Potassium carbonate (3.96 g, 29 mmol) and 2-bromo-2-methylpropanoic acid ethyl ester (4.47 g, 23 mmol; CAS Reg. No. 600-00-0) were added to a solution of 3-fluoro-4-nitrophenol (3 g, 19 mmol; CAS Reg. No. 394-41-2) in DMSO (50 ml). The mixture was stirred for 18 h at 100° C. 10% aqueous citric acid and EtOAc were added and the layers were separated. The organic layer was washed with brine and dried over MgSO4. The solid was filtered off and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/heptane) to obtain the title compound (1.19 g, 4.4 mmol; 23%) as yellow oil.
Reaction SMILES: FC(F)(F)C(C1SC(C(O)=O)=CC=1)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.FC1C=CC(CS(CC(=N)NO)(=O)=O)=CC=1.[F:43][C:44]1[CH:71]=[CH:70][C:47]([CH2:48][S:49]([CH2:52]/[C:53](=[N:55]/[O:56][C:57]([C:59]2[S:60][C:61]([C:64](=[O:69])[C:65]([F:68])([F:67])[F:66])=[CH:62][CH:63]=2)=O)/[NH2:54])(=[O:51])=[O:50])=[CH:46][CH:45]=1>CN(C=O)C.O.CC#N>[F:66][C:65]([F:68])([F:67])[C:64]([C:61]1[S:60][C:59]([C:57]2[O:56][N:55]=[C:53]([CH2:52][S:49]([CH2:48][C:47]3[CH:70]=[CH:71][C:44]([F:43])=[CH:45][CH:46]=3)(=[O:51])=[O:50])[N:54]=2)=[CH:63][CH:62]=1)=[O:69]
Reactant: N/C(CS(=O)(=O)Cc1ccc(F)cc1)=N\OC(=O)c1ccc(C(=O)C(F)(F)F)s1
Agent: N=C(CS(=O)(=O)Cc1ccc(F)cc1)NO
Agent: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(-c2nc(CS(=O)(=O)Cc3ccc(F)cc3)no2)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The above acid (A1) was dissolved in DMF and a solution of CDI (1.1 eq) in DMF was added. The mixture was stirred at RT for 30 min, then 2-[(4-fluorobenzyl)sulfonyl]-N-hydroxyethanimidamide (1.1 eq.) in DMF was added and the mixture stirred at RT overnight. The resulting intermediate (1Z)-2-[(4-fluorobenzyl)sulfonyl]-N′-({[5-(trifluoroacetyl)-2-thienyl]carbonyl}oxy)ethanimidamide (MS (ES) C16H12F4N2O5S2 requires: 452, found: 471 (M+H2O+H)+) was not isolated, instead CDI (1.1 eq) in DMF was added and the mixture was heated in a microwave oven (sealed tube, 140° C., 2 min). The product was isolated by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The pooled product fractions were evaporated to afford the title compound. 1H NMR (300 MHz, CD3CN): 8.1-8.07 (2H, m), 7.91 (0.1H, d, J=4 Hz, hydrate form), 7.58-7.49 (2H, m), 7.41 (0.1H, d, J=4 Hz, hydrate form), 7.25-7.12 (2H, m), 4.57 (2H, s), 4.54 (2H, s), 4.48 (0.2H, s, hydrate form). 19F NMR decoupled (282 MHz, CD3CN): −73.78 (keto form), −85.45 (hydrate form), −114.51. MS (ES) C16H10F4N2O4S2 requires: 434, found: 453 (M+H2O+H)+, MS (ES−) 433 (M−H+e)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[CH:55]([OH:57])[CH3:56]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:57][CH:55]([C:54]2[CH:58]=[CH:59][CH:60]=[C:52]([F:51])[CH:53]=2)[CH3:56])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CC(O)c1cccc(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cccc(F)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 68.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (86 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (150 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-fluoro-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (89 mg, yield 64%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH:12]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]2[CH:19]=[C:20]([C:23]3[N:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[CH:22][C:13]1=2.[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31].O>CO>[C:34]([CH:32]([CH:30]([C:29]([OH:38])=[O:37])[OH:31])[OH:33])([OH:36])=[O:35].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH:12]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]2[CH:19]=[C:20]([C:23]3[N:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[CH:22][C:13]1=2
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: c1cnnc(-c2ccc3c(c2)CNCCC3Oc2ccc3ccccc3c2)c1
Solvent: CO
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
To a solution of the product (45 mg, 0.12 mmol) from Step J above in methanol (1 mL) was added L-tartaric acid (17 mg, 0.12 mmol) followed by slow addition of water (5 mL). The resultant solution was lyophilized overnight to give (+)-5-(naphthalen-2-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, tartrate salt (58 mg, 94%, AUC HPLC>99%) as white solid: mp 122-124° C.; 1H NMR (CD3OD, 500 MHz) δ 9.18 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 8.19 (d, J=8.7 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.81-7.76 (m, 4H), 7.70 (d, J=8.2 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 7.37 (s, 1H), 7.34-7.31 (m, 2H), 5.94 (d, J=8.2 Hz, 1H), 4.88-4.81 (m, 1H), 4.60-4.56 (m, 1H), 4.40 (s, 2H), 3.98-3.90 (m, 1H), 3.70-3.60 (m, 1H), 2.92 (s, 3H), 2.54-2.48 (m, 2H); ESI MS m/z 382 [M+H].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:22])=[O:21])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH2:36])=[CH:34][C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH:36][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20]([CH3:22])=[O:21])[C:3]=3[CH3:23])=[CH:34][C:33]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using (+/−)-4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinoline (22.0 mg, 0.063 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give (+/−)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.21 (1H, d, J=8.0 Hz), 7.91 (1H, br. s.), 7.76 (1H, td, J=7.6, 1.4 Hz), 7.66-7.71 (1H, m), 7.65 (1H, d, J=2.5 Hz), 7.54 (1H, d, J=8.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.08 (1H, ddd, J=13.5, 8.5, 2.4 Hz), 6.38 (1H, br. s.), 3.92 (4H, br. s.), 3.84 (4H, t, J=4.8 Hz), 3.19-3.54 (3H, m), 3.00-3.18 (5H, m), 2.55-2.97 (3H, m), 2.01 (3H, br. s.). Mass Spectrum (ESI) m/e=580.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12](=[O:27])[N:13]2[CH:17]([C:18]([NH:20][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:41][NH2:42].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:42][O:41][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)[C:12]([N:13]2[C@H:17]([C:18]([NH:20][C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ncccn1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ncccn1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(2-pyrimidinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoic acid (183 mg, 0.49 mmol) in dichloromethane (DCM) (10 mL) was added N-methylmorpholine (0.14 mL, 1.27 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (69 mg, 0.59 mmol), EDC (112 mg, 0.59 mmol) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (67 mg, 0.49 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was then washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-70% MeCN:H2O) to afford (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)amino]butanoyl}-N-2-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (80 mg, 34% yield). MS: 473 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH:26]([Mg]Cl)([CH3:28])[CH3:27].[NH4+].[Cl-]>C1COCC1.CN1C(=O)CCC1>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2]([CH:26]([CH3:28])[CH3:27])=[N:3][C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:5][C:6]=2[CH3:19])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)[Mg]Cl
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCc1cccc(F)c1
Temperature: -30 °C
Yield: 36.1 %

Procedure:
A solution of 300 mg (0.83 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF/NMP (6:1 v/v, 14 ml) was cooled to −30° C. At this temperature were successively added 58 mg (0.16 mmol) Fe(acac)3 and 6 ml (12.0 mmol, 2M in THF) iso-propyl-magnesium-chloride. The RM was then allowed to warm to 0° C. within 1 h. Then sat. aq. NH4Cl sol. was added the mixture was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 110 mg (0.30 mmol, 36%) N-[(3-Fluorophenyl)-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 23). [M+H]+ 372.2.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[C:8]([O:12][C:13]([N:15]([CH2:32][CH:33]=O)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClC(Cl)C>[C:8]([O:12][C:13]([N:15]([CH2:32]/[CH:33]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:20][CH2:21]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)OC(=O)N(CC=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N(C/C=N/S(=O)C(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
2-Methyl-2-propanesulfinamide (212 mg, 1.753 mmol) and cupric sulfate monohydrate (849 mg, 4.78 mmol) were added to a solution of benzyl 4-[(tert-butoxycarbonyl)(2-oxoethyl)amino]piperidine-1-carboxylate (600 mg, 1.59 mmol) in dichloroethane (15 mL) and was heated at 50° C. After 18 h, the reaction was filtered, concentrated, and purified by silica gel chromatography chromatography (75%-95% ethyl acetate/hexanes) to give the title compound (400 ing). MS 380.24 (M+1-boc group)
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2C(O)=O.[Br:11]Br.C[C:14]([O:16]C=C)=[O:15].C=CCl.S([O-])([O-])=O.[Na+].[Na+].P(Cl)(Cl)Cl>CCOCC.ClP(Cl)Cl>[Br:11][CH:2]1[CH2:3][C@@H:4]2[CH2:7][C:1]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2
Reactant: O=C(O)C1C[C@@H]2CC[C@H]1C2
Reactant: BrBr
Reactant: C=COC(C)=O
Agent: C=CCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClP(Cl)Cl
Product: O=C(O)C12CC[C@H](CC1Br)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid (9.84 g, 70 mmol) and bromine (4.10 ml, 80 mmol). The suspension was stirred at room temperature until dissolution. Trichlorophosphine (0.30 ml, 3.4 mmol) was then added slowly and drop wise (significant exotherm observed). A reflux condenser was fitted to the flask with a nitrogen gas inlet and gas outlet (Tygon tubing) running into a scrubber solution of sodium sulfite (1 M, 200 mL). After the addition was complete, the reaction mixture was heated in a silicone oil bath at 80° C. for 4 h. After this time, the reaction was cooled to 10° C. and phosphorus-trichloride (4.23 ml, 48.3 mmol) was added drop-wise. The reaction was then heated to 80° C. During this time the color intensity of the reaction decreased, and after 8 h, the reaction mixture appeared dark orange. The reaction was then cooled to room temperature and diluted with ether (1 L). The ethereal solution was transferred to a separation funnel and washed with 1M sodium sulfite (2×500 mL), water (1×500 mL), and brine (1×500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford an oil. Ice cold pentane (50 mL) was then added to the crude product, and the mixture was stirred vigorously. After 20 min, a fine white precipitate formed, which was filtered and washed with pentane (20 mL) and then air dried under a gentle vacuum to afford (4S)-2-bromobicyclo[2.2.1]heptane-1-carboxylic acid (100.2 g, 457 mmol) as a white solid material.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]([C:12]#CC(C)=C)=[CH:10][N:9]([CH2:17][C:18]3[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:49]C)C=C4)N(CC2)C1.[CH3:86][C:87]([OH:90])([CH3:89])[CH3:88].O>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:12]#[C:86][C@@:87]([CH3:89])([OH:90])[CH2:88][OH:49])=[CH:10][N:9]([CH2:17][C:18]3[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=3)[C:4]=2[N:5]=1
Reactant: CC(C)(C)O
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=C(C)C#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Solvent: O
Product: COc1c(C)cnc(Cn2cc(C#C[C@@](C)(O)CO)c3c(Cl)nc(N)nc32)c1C

Procedure:
Treatment of 4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-5-(3-methylbut-3-en-1-ynyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (see example 51) (357 mg) with AD-mix-β (Aldrich, 1.57 g) in t-BuOH:water 1:1: (10 mL) at rt for 18 h, followed by quench (NaHSO3, 1.2 g), work-up, and silica gel flash chromatography (1→10% MeOH inDCM) gave the title compound (61 mg) and recovered starting material (263 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[OH:21])[NH2:17]>>[ClH:1].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccc(O)c(Cl)c1
Product: Cl
Product: Oc1ccc(Nc2ncnc3ccc(I)cc23)cc1Cl
Yield: 88 %

Procedure:
According to the same manner as that of the first step of Example 1 and using 20.3 g of 4-chloro-6-iodoquinazoline and 10 g of 3-chloro-4-hydroxyaniline, 4-(3-chloro-4-hydroxyphenylamino)-6-iodoquinazoline hydrochloride (III-4, 26.6 g) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:13]=[CH:12][C:11]=2[CH3:34])=[O:8])=[CH:5][C:4]([CH3:35])=[N:3]1.C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48]>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:19]1[C:20](=[N:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH:21]=[CH:22][C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]([CH3:34])=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:35])[CH:5]=3)=[O:8])[CH:15]=2)=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 72.4 %

Procedure:
In the same manner as in Reference Example 5 and using 1,3-dimethyl-N-{2-methyl-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (2.91 g, 5.92 mmol), N,N-diisopropylethylamine (1.34 mL, 7.70 mmol), iodoacetamide (1.42 g, 7.70 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (2.35 g, 72%) was obtained as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:10][C:11](=[O:14])[CH2:12][NH2:13]>>[CH:1]1([NH:13][CH2:12][C:11]([OH:14])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: COC(=O)CN
Product: O=C(O)CNC1CCCCCC1

Procedure:
N-Cycloheptylglycine was synthesized by reductive amination of cycloheptanone with glycine methyl ester following the procedure described in Gera et al., Immunopharmacology. 33:174–177 (1996). The crude product was converted to the N-Boc derivative (mp, 89–90° C.).