Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:12].C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[Cl:12][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([C:19]1([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]1)=[CH:11]2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccnc2cc(Br)cnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3c(Cl)ccnc3c2)CC1
Temperature: -78 °C
Yield: 38 %

Procedure:
Dissolved 3-bromo-8-chloro-1,5-naphthyridine (210 mg, 862 μmol) in 8 mL of THF and cooled to −78° C. Then added butyllithium (517 μl, 1294 mol) and stirred for 15 min. Added tert-butyl 4-oxopiperidine-1-carboxylate (258 mg, 1294 μmol) and let warm to room temperature over 1 h. The reaction was quenched with saturated NH4Cl and extracted with dichloromethane (3×20 mL), dried over NaSO4 and concentrated. Intermediate was purified via MPLC (DCM/MeOH/NHOH) to yield tert-butyl 4-(8-chloro-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (120 mg, 38% yield.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)[C:10]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(OCC)C>[CH3:20][NH:19][C:15]1[CH:14]=[C:13]([C:11]2[C:10]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=4)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[N:9][NH:8][CH:12]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CNc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 70 °C
Reaction time: 6 h
Yield: 63.2 %

Procedure:
200 mg (0.35 mmol) of 1-(3-{1-(4-methoxybenzyl)-4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea were dissolved with 10 ml of trifluoroacetic acid and the solution was stirred at 70° C. for 6 hours. The solvent was then evaporated and the residue taken up with dichloromethane and washed with aqueous sodium hydrogenocarbonate. The organic layer was dried over sodium sulphate and evaporated again, affording, after trituration with diethylether, 100 mg (63%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][C:18]1[CH:23]=CC=CC=1)=[O:16].NC1C=[N:29][CH:28]=[C:27]([Cl:31])[N:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:31][C:27]1[N:26]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:23]=[N:29][CH:28]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CN1C(C(=O)Nc2ccccc2)=C(O)c2ccccc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Yield: 22.7 %

Procedure:
1.0 g (3 mmols) of 4-hydroxy-2-methyl-N-phenyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were refluxed with 1.3 g (10 mmols) of 2-amino-6-chloro-pyrazine and 0.1 g of p-toluenesulfonic acid in 250 ml of xylene for 72 hours. After cooling, the reaction mixture was washed with 2N hydrochloric acid and then with water, then dried and concentrated by evaporation in vacuo. The residue was purified column chromatography (Merck silicagel 60; particle size: 0.2-0.5 mm; eluant: chloroform/ethanol 90:10) and yielded 0.25 g (23% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:7][C:8](=[O:15])[C@@H:9]([NH2:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1.C(OC(Cl)=O)C(C)C.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:7][C:8](=[O:15])[C@@H:9]([NH:14][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[O:25])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH3:6])[CH3:2]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)C1CCN(C)CC1)C(C)(C)C

Procedure:
For compound (A48) (S)-2-((S)-2-Amino-3,3-dimethyl-butyrylamino)-propionic acid ethyl ester was coupled with 1-Methyl-piperidine-4-carboxylic acid using isobutylchloroformate and N-methylmorpholine in DMF to give (S)-2-{(S)-3,3-Dimethyl-2-[(1-methyl-piperidine-4-carbonyl)-amino]-butyrylamino}-propionic acid ethyl ester. This was then quaternised with MeI in DCM-acetone and subsequently hydrolysed using an hydroxide resin such as Ambersep 900-OH resin.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:1]([O-:4])=[O:2])[CH:7]=1
Reactant: O=c1[nH]c2c(F)cccc2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Nitric acid (70%, 2.50 ml, 0.0389 mol) is added dropwise at −10° C. to a solution of 4-fluoro-1,3-benzoxazol-2(3H)-one (Step 4, 5.95 g, 0.0389 mol) in concentrated sulfuric acid (60 ml). The reaction is stirred at −10° C. for 30 minutes and then poured into ice water. The resulting precipitate is collected by filtration and dried under reduced pressure to give desired product contaminated with approximately 10-15% of the undesired 5-nitro isomer (7.2 g, 93%); mp 177-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:8](F)[C:7]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:6][CH:5]=1)[CH3:2].[CH:33]1([O-:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.[Na+]>>[CH:33]1([O:38][C:8]2[C:7]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=2[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: [O-]C1CCCC1
Reactant: CCOc1ccc(S(C)(=O)=O)c(F)c1C(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2)CC1
Agent: [Na+]
Product: CCOc1ccc(S(C)(=O)=O)c(OC2CCCC2)c1C(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 80 °C

Procedure:
0.12 mmol of (6-Ethoxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone (example 55) was added to a solution of sodium cyclopentanolate (prepared from 1 mmol sodium dissolved in 1 ml of cyclopentanol). The mixture was heated for 1 hour at 80° C., poured on ice/water and extracted with ethyl acetate. Chromatography (SiO2; ethyl acetate) yielded the title compound as a slightly yellow solid. MS (m/e): 551.1 (MH+, 29%)
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([NH:17][C:18](=[O:20])[CH3:19])=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)C.CO.[OH-].[Na+].Cl>O>[OH2:3].[C:18]([NH:17][C:5](=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[C:4]([OH:21])=[O:3])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(=Cc1c[nH]c2cc(C)ccc12)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NC(=Cc1c[nH]c2cc(C)ccc12)C(=O)O
Reaction time: 0.75 h

Procedure:
three-necked flask, equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 159.5 g (0.56 mol) of crude alpha-acetamido-6-methylindole-3-acrylic acid ethylester and 475 ml of methanol. The mixture was heated in an oil bath to 50°. A solution of 66.8 g (1.67 mol) of sodium hydroxide in 320 ml of water was added over 3 minutes and the resulting brown solution was stirred at 50° for 45 minutes. The reaction mixture was cooled with an ice bath to 25° and 600 ml of 4 N hydrochloric acid was added over 20 minutes at 25°. The precipitate was collected on a Buchner funnel, washed with 900 ml of water and dried at 50° overnight and at 60°/0.5 mm for 3 hours. The beige solid (146 g) was dissolved in 1 l of methanol and 175 ml of dimethylformamide at reflux. 10 g of charcoal was added and reflux was continued for 10 minutes. The mixture was filtered through a bed of Celite and the clear brown solution was brought again to reflux. 425 ml of water was added over a 20 minute period, while reflux was maintained. The mixture was refrigerated for 3 hours. The product was collected by suction filtration, washed with 750 ml of 1:1 methanol-water and dried at 50° for 24 hours (const. weight) to yield 119.9 g (69% based on 6-methylindole-3-carboxyaldehyde of product as yellow crystals, m.p. 229° (dec.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[NH:19])OC)[N:8]=1.[C:23]([NH:26][NH2:27])(=[O:25])[CH3:24]>CO>[C:23]([NH:26][NH:27][C:16](=[NH:19])[CH2:15][CH2:14][CH2:13][CH2:12][N:9]1[CH:10]=[N:11][C:7]([NH:6][C:5]([NH2:20])=[N:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[N:8]1)(=[O:25])[CH3:24]
Reactant: COC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reactant: CC(=O)NN
Solvent: CO
Product: CC(=O)NNC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A solution of methyl 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valerimidate (0.5 g.) in MeOH (5 ml.) and acethydrazide (0.17 g.) was allowed to stand at room temperature for 3 hours. The solution was evaporated to give a sticky solid which was triturated with ether/EtOH to give N-acetylamino-5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeramidine as a white solid (0.71 g.), m.p. 157°-159°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[N:45]([CH3:49])[CH:46]=[CH:47][N:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[N:45]([CH3:49])[CH:46]=[CH:47][N:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: Cn1ccnc1Br
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3nccn3C)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 2-bromo-1-methyl-1H-imidazole.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:4]1.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[CH2:4]3)=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: N[C@@H]1CCN(C(=O)c2cccc(O)c2)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(C(=O)c3cccc(O)c3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxybenzoyl)pyrrolidine hydrochloride, as described above in Step B, (350 mg, 1.44 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde as described in Example 1, Step G (363 mg, 1.58 mmol), were stirred in MeOH (8 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (109 mg, 1.73 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (3×15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CHCl3—3% MeOH—0.4% NH4OH to CHCl3—6% MeOH—0.6% NH4OH to yield the titled product as a white foam.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([NH:17][C:18]1[N:23]=[C:22]([C:24]2[C:32]3[C:27](=[N:28][C:29]([NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:30][CH:31]=3)[NH:26][N:25]=2)[CH:21]=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.Cl>CCO>[N:36]1([CH2:35][CH2:34][NH:33][C:29]2[N:28]=[C:27]3[NH:26][N:25]=[C:24]([C:22]4[CH:21]=[CH:20][N:19]=[C:18]([NH:17][CH:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:9][CH2:8][NH2:7])[N:23]=4)[C:32]3=[CH:31][N:30]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester (150 mg, 0.26 mmol) was dissolved in EtOH (4 mL), then conc. HCl (4 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to afford the crude product which was purified by prep-HPLC to afford N1-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine; hydrochloride. (Yield 30 mg, 19.5%).
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][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]>C1COCC1.CN(C1C=CN=CC=1)C>[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 75.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3 mmol), described in Example 318A. The crude was purified by silica gel chromatography (DCM/MeOH 0-15%) and triturated in diethyl ether to afford 1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (127 mg, 75%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.99 (t, J=18 Hz, 3H), 3.99 (s, 6H), 6.67 (s, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.34 (d, J=5 Hz, 2H), 7.38-7.59 (m, 7H), 7.77 (s, 1H), 8.66 (s, 1H), 8.68 (s, 1H), 9.27 (s, 1H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 33.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.2 g), 1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide (1.3 g) was obtained, melting point: 249–250° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15](Cl)=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]#[N:19])=[CH:5][CH:4]=1.[CH:22]([N:25](CC)C(C)C)(C)C>CN(C)C=O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15]([NH:25][CH3:22])=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]#[N:19])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(C(=O)Cl)nc1SCc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C#N)c(SCc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
A mixture of 6-(4-chlorobenzylthio)-5-cyanopicolinoyl chloride hydrochloride 81 (60 mg, 0.17 mmol) and N,N-diisopropylethylamine (89 ul, 0.51 mmol) in dimethylformamide (2 ml) was stirred for 6 hrs at room temperature. After removal of the solvent, the residue was triturated with ether and the resulting solid was collected by filtration to afford 40 mg (74%) of the desired product 84. 1H NMR (600 MHz, DMSO-d5) δ 8.79 (d, 1H, J=4.8 Hz), 8.37 (d, 1H, J=7.8 Hz), 7.84 (d, 1H, J=8.4 Hz), 7.49 (d, 2H, J=9 Hz), 7.38 (d, 2H, 9 Hz), 4.76 (s, 2H), 2.89 (d, 3H, J=4.8 Hz). MS: m/z Calcd 317.8 Found MH+ 318.0
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([NH2:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1Cl>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1[NH:12][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(C(N)=O)cc1OC1CCCC1
Reactant: Clc1cncc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1

Procedure:
Alternatively, a suspension of 3-cyclopentyloxy-4-methoxybenzamide (2.58 g; that is prepared as described in Reference Example 73) in dry toluene (40 mL) is heated at reflux and treated with potassium t-butoxide (1.4 g), followed by 3,4,5-trichloro-pyridine (1.82 g). The mixture is then heated at reflux for 3 hours and 45 minutes, and is then treated with a further quantity of potassium t-butoxide (1.4 g) and heated at reflux for a further period of 7 hours. The mixture is allowed to cool and is then filtered. The filtrate is evaporated and the resulting residue is extracted with aqueous sodium hydroxide solution (2 M). The alkaline solution is then acidified by treatment with acetic acid, and the solid which separates is collected by filtration, washed with water and dried, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide (2.09 g) in the form of a buff solid, m.p. 153°-155° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][CH2:16][CH:17]([OH:19])[CH3:18]>>[C@H:17]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:16][CH3:15])[CH3:18]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CCC(C)O
Product: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example B4(c) from 2-Fluoro-5-methanesulfonyl-benzoic acid (example B4(b)) and R-(−)-2-butanol. White solid. MS (m/e): 271.1 ([M−H], 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[C:42]([O:52][CH3:53])[C:43]([N+:49]([O-:51])=[O:50])=[CH:44][CH:45]=2)[O:40][C:39]=1[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42]([O:52][CH3:53])[C:43]([N+:49]([O-:51])=[O:50])=[CH:44][CH:45]=4)[O:40][C:39]=3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1c([N+](=O)[O-])ccc2c(=O)c(I)c(-c3ccccc3)oc12
Product: COc1c([N+](=O)[O-])ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 72 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-8-methoxy-7-nitro-2-phenyl-chromen-4-one was reacted to give the title compound as a yellow solid (390 mg, 72%). LCMS (Method G): RT=4.47 min, [M+H]+=543.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([C:25]([O:27][CH3:28])=[O:26])[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:22]2[CH2:24][CH2:23]2)[CH2:9]1.[C:38](Cl)([Cl:40])=[O:39]>C1(C)C=CC=CC=1>[F:33][C:32]([F:34])([F:35])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[CH2:6][N:7]([C:25]([O:27][CH3:28])=[O:26])[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:38]([Cl:40])=[O:39])[C@@H:10]([CH:22]2[CH2:24][CH2:23]2)[CH2:9]1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2ccc(C(F)(F)F)cc21
Solvent: Cc1ccccc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2ccc(C(F)(F)F)cc21

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example 102A) (180 mg, 0.33 mmol) in 2 mL of a 1.93M solution of phosgene in toluene was heated to reflux for 1 h. Excess phosgene was removed by purging with nitrogen, and the resulting solution was concentrated to afford the crude title product (208 mg) which was used without further purification. MS m/z 621 (M+19+); 1H NMR (CDCl3) δ 0.2 (m, 1H), 0.45 (m, 2H), 0.55 (1H), 0.75 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17](O)[CH3:18].CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][CH2:11][C:16]([C:15]1[CH:14]=[CH:13][CH:12]=[CH:17][CH:18]=1)=[O:22]
Reactant: CC(C)=O
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(C)O)c1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: Cc1ccc(Cl)c(NCC(=O)c2ccccc2)c1Cl

Procedure:
The desired compound was prepared by oxidation of 1-{2-[(2,6-dichloro-3-methylphenyl)amino]phenyl}ethanol, prepared as in step 1, with Jones reagent.