Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH2:24])=[O:23])[CH:17]=1>>[C:22]([C:18]1[CH:17]=[C:16]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:21]=[CH:20][N:19]=1)(=[O:23])[NH2:24]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: NC(=O)c1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1

Procedure:
6-Hydroxy-1-napthoic acid (2.5 g, 13 mmol) was reacted with 4-chloropicolinamide (WO 02/085857) (2.6 g, 15 mmol) under the conditions of Example 421 Step a to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 309.2 (M+1). Mass Calc'd for C17H12N2O4: 308.29.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:10])=[O:9])[C:3]=1[OH:11].[C:12](=S)(OCC)[S-:13].[K+]>C(O)C>[SH:13][C:12]1[O:11][C:3]2[C:4]([S:8]([CH3:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: CS(=O)c1cccc(N)c1O
Agent: [K+]
Solvent: CCO
Product: CS(=O)c1cccc2nc(S)oc12
Yield: 77 %

Procedure:
To a solution of this aminophenol. (233 mg, 1.36 mmol) in ethanol (10 ml) was added potassium O-ethyl dithiocarbonate (300 mg, 1.87 mmol) and the mixture was stirred under heating to reflux for 9 hours. The reaction solution was acidified to pH, 4 with 1 N hydrochloric acid and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentraed in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:methanol=10:1) and recrystallized from chloroform-ether to provide 223 mg (yield 77%) of 2-mercapto-7-methansulfinylbenzoxazole as pale brown powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](OCC)=[O:10])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1
Reactant: CCOC(=O)c1cc(Cl)cc(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)cc(CO)n1
Yield: 95 %

Procedure:
A solution of ethyl 4-chloro-6-methylpyridine-2-carboxylate (0.80 g) in methanol (30 ml) was treated at room temperature portionwise with sodium borohydride (1.51 g) and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was concentrated and the resultant residue was combined with water and ethyl acetate, and the organic phase was isolated, dried and concentrated to obtain the title compound (0.60 g) as a tan powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:45][C:46]([CH3:57])=[C:47]([CH2:49][CH2:50][N:51]3[CH2:55][CH2:54][CH2:53][C@H:52]3[CH3:56])[N:48]=2)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[O:45][C:46]([CH3:57])=[C:47]([CH2:49][CH2:50][N:51]4[CH2:55][CH2:54][CH2:53][C@H:52]4[CH3:56])[N:48]=3)=[CH:40][CH:39]=2)[CH:27]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cncc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)c1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of palladium (II) acetate (0.004 g, 0.02 mmol) in anhydrous toluene (5 mL), add triphenylphosphine (0.019 g, 0.07 mmol), under nitrogen and at room temperature. Stir for 15 minutes then add distilled water (1.5 mL), ethanol (1 mL), 3-methoxypyridine-5-boronic acid pinacol ester (0.26 g, 1.10 mmol), 2-(4-bromophenyl)-4-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}-5-methyl-1,3-oxazole (See Intermediate 73(0.32 g, 0.92 mmol) and potassium carbonate (0.38 g, 2.75 mmol). Heat the reaction mixture at 110° C. overnight. Cool to room temperature then pour into water. Extract with dichloromethane then concentrate the combined extracts in vacuo. Load onto a 10 g Isolute® SCX-2 column (preconditioned with methanol). Wash the SCX-2 with methanol then elute the target compound with 2N ammonia in methanol solution followed by 7N ammonia in methanol. Concentrate the combined ammonia solutions in vacuo to give a pale yellow solid (0.16 g). Purify using automated flash chromatography (ISCO® System, 12 g Redisep® SiO2 column; 0-30% methanol in ethyl acetate gradient elution over 20 minutes at 30 mL/min) to give the title compound as a pale yellow solid (0.23 g): MS (m/e): 378(M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[O-:13][CH2:14]C.[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([O:13][CH3:14])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC)nc(Cl)n1
Reaction time: 16 h
Yield: 24 %

Procedure:
Methyl 2,6-dichloropyrimidine-4-carboxylate (10 g) (M. Winn et. al., J.Med.Chem. 36 (18), (1993), 2676-2688) in methanol (100 ml) was treated with sodium ethoxide (3 g) and left for 16 hours. Methanol was evaporated and the residue partitioned between dichloromethane and saturated aqueous NaHCO3. The organic was washed with brine, dried and evaporated to give the title compound (24%). NMR δ(CDCl3) 4.00(3H, s), 4.07(3H, s), 7.37(1H, s). (b) Sodium 2-chloro-6-methoxypyrimidine-4-carboxylate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.[N:12]1([CH2:17][C:18](=[CH2:23])[C:19]([O:21]C)=[O:20])[CH:16]=[N:15][CH:14]=[N:13]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:23][C:18]([C:19]([OH:21])=[O:20])([CH2:17][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[O:9][N:8]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=NO)cc1
Reactant: C=C(Cn1cncn1)C(=O)OC
Solvent: ClCCl
Product: COc1ccc(C2=NOC(Cn3cncn3)(C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
4-Methoxybenzaldehyde oxime (1.63, g, 10.8 mmol) and methyl 2-(1,2,4-triazol-1-ylmethyl)acrylate.(1.50 g, 8.97 mol) were added together with 100 mL of CH2Cl2. To the above mixture was added bleach (23 mL of 0.67M aqueous solution) dropwise at room temperature. The reaction mixture was then stirred at RT under N2 for 12 h. The mixture was diluted with CH2Cl2 and washed with water and brine, It was dried over MgSO4, concentrated, and chromatographed with 30-100% EtOAc in CH2Cl2 on silica gel to give 1.81 g of the desired product (66%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH2:4][O:3]1.Cl.[NH2:14][OH:15].[OH-].[Na+]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[N:14][OH:15])[CH:9]=2)[CH2:4][O:3]1
Reactant: NO
Reactant: O=Cc1ccc2c(c1)C(=O)OC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCc2ccc(C=NO)cc21

Procedure:
According to a similar procedure to that described in Example 4-(4), 1-oxo-1,3-dihydroisobenzofuran-6-carbaldehyde (2.42 g, 14.9 mmol) obtained from Example 5-(1), hydroxylamine hydrochloride (1.35 g, 19.4 mmol), and an aqueous solution of sodium hydroxide (1.0N; 19.3 ml, 19.3 mmol) were reacted, and the reaction mixture was worked up to afford 1-oxo-1,3-dihydroisobenzofuran-6-carbaldehyde oxime as a crude solid. According to a similar procedure to that described in Example 4-(4), the crude product obtained above, triethylamine (3.92 g, 39 mmol), and anhydrous trifluoroacetic acid (4.08 g, 19.4 mmol) were reacted, and the reaction mixture was worked up to afford, after extraction and concentration, a solid residue. The residue was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:dichloromethane=0:1˜1:10) to afford the title compound (1.67 g, 70% yield) as a solid (mp. 195-196° C.).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:27])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[C:23]2=[N:24][S:25][N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].Cl>C1COCC1.O>[N:26]1[S:25][N:24]=[C:23]2[C:18]([S:15]([NH:14][C:8]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=3[C:6]([OH:27])=[O:5])(=[O:17])=[O:16])=[CH:19][CH:20]=[CH:21][C:22]=12
Reactant: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Reaction time: 18 h
Yield: 99.9 %

Procedure:
LiOH.H2O (0.68 g, 16.2 mmol) was added to a stirred solution of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid methyl ester (1.56 g, 4.06 mmol) in THF (15 mL) and water (5 mL). After 18 h, the solution was acidified to pH 2 with conc. HCl, diluted with water, and extracted with DCM (3×). The combined organic layers were dried (MgSO4), and concentrated to provide the title compound (1.50 g, 100%). HPLC: RT=9.48 min. MS (ESI−): mass calcd. for C13H8ClN3O4S2, 368.96; m/z found, 368/370 [M−H]. 1H NMR (500 MHz, CDCl3): 11.07 (s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.24 (dd, J=8.8, 1.0, 1H), 7.92 (d, J=2.5, 1H), 7.75 (d, J=9.0, 1H), 7.71-7.69 (m, 1H), 7.40 (dd, J=9.0, 2.6, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:26])=[O:11])=[CH:7][CH:8]=1
Reactant: O=S(Cc1ccc(CCl)cc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Cc1ccc(CCl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.61 g (0.104 mol) (1a) was dissolved in 400 ml CH2Cl2. This solution was added dropwise to an ice-cooled solution of 36.03 g (0.208 mol) 3-chloroperbenzoic acid in 600 ml CH2Cl2 and 33.61 g (0.375 mol) NaHCO3 in 200 ml H2O. After the addition of (1a) the mixture was allowed to warm up to room temperature, and this was followed by another 2 hours' stirring. The reaction mixture was then poured into 500 ml 5% Na2CO3 solution. The organic layer was washed with 500 ml 5% Na2S2O3 solution. The CH2Cl2 was dried over MgSO4 and evaporated. The precipitate was purified by recrystallization from hexane/toluene. Yield: 26.65 g (91%); m.p.=170.3-170.9° C. (dec.)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][OH:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl.O>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:26]2[CH2:31][CH2:30][CH:29]([CH:32]=[O:33])[CH2:28][CH2:27]2)(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To a stirred solution of oxalyl chloride (92 μL, 1.07 mmol) in DCM (2 mL) at −78° C. is added dropwise a solution of dimethyl sulfoxide (0.15 mL, 2.16 mmol) in DCM (2 mL). After 15 mins a solution of (1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidin-4-yl)methanol (0.26 g, 0.79 mmol) in DCM (2 mL) is added dropwise. After another 15 mins, triethylamine (0.425 mL, 3.04 mmol) is added and the reaction is allowed to warm to room temperature. Stirring is continued for 18 h. The mixture is diluted with water and extracted with DCM. The organic layers are combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.26 g (99%) of 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidine-4-carbaldehyde. m/z=331.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Br:12])C=C.C(N(CC)[C:16]1[CH:21]=CC=C[CH:17]=1)C>>[CH2:21]([C:10]1[CH:9]=[C:8]([Cl:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:4])[CH:16]=[CH2:17]
Reactant: C=CCOc1ccc(Cl)cc1Br
Reactant: CCN(CC)c1ccccc1
Product: C=CCc1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 1-(allyloxy)-2-bromo-4-chlorobenzene (4.122 g, 16.65 mmol) in N,N-diethylaniline (20 mL, 100 mmol) was heated at 200° C. for 15 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and 1M aqueous HCl, and the organic layer washed with an additional portion of 1M aqueous HCl and then brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 20% ethyl acetate in heptanes) to yield 3.1761 g (77%) of 2-allyl-6-bromo-4-chlorophenol as a clear, colorless oil. 1H NMR (400 MHz, CDCl3) δ: 7.33 (d, J=2.4, 1H), 7.07 (d, J=2.3, 1H), 5.94 (ddt, J=16.8, 10.3, 6.6, 1H), 5.53 (s, 1H), 5.18-5.06 (m, 2H) 3.40 (d J=6.6, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 60 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (57 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (83 mg, 0.108 mmol, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.35 (s, 1H), 8.44 (s, 1H), 8.19 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.52, 2.11 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.33-7.44 (m, 3H), 7.27 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.93 (t, J=6.87 Hz, 1H), 6.67 (d, J=2.38 Hz, 1H), 6.51 (d, J=5.31 Hz, 1H), 6.48 (dd, J=8.79, 2.56 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.30-3.35 (m, 2H), 3.11-3.20 (m, 4H), 3.03 (s, 3H), 2.74 (t, J=6.78 Hz, 2H), 2.52-2.62 (m, 4H). MS (ESI): 769 [M+H]+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]1[N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: O=CCC1Cc2cc(F)ccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1ccc(F)cc1C2
Reaction time: 0.75 h
Yield: 69 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-5-fluoro-1-indanone and 85 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.12 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.66 g (69%) of (RS)-1-(6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30].[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: COc1ccc(CN2Cc3c(Br)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: OB(O)c1ccc(F)cc1Cl
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CN2Cc3c(-c4ccc(F)cc4Cl)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
To a solution of 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (200 mg, 0.31 mmol) and 2-chloro-4-fluoro-benzene boronic acid (98 mg, 0.62 mmol) in toluene (3 mL) and ethanol (0.3 mL) was added sodium carbonate (2M solution, 0.39 mL) and tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0155 mmol). The flask was evacuated and purged with nitrogen a few times. The reaction mixture was heated to reflux for 2 h and diluted with methylene chloride. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 5% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 3H), 1.08 (s, 3H), 1.64 (m, 2H), 2.40 (m, 1H), 2.57 (brs, 1H), 2.83 (t, 1H, J=7.3 Hz), 2.90 (brs, 1H), 3.14 (s, 1H), 3.53 (m, 2H), 3.63 (t, 1H, J=13.2 Hz), 3.81 (s, 3H), 4.11 (abq, 2H, J=14.9 Hz), 4.55 (abq, 2H, J=14.9 Hz), 6.22 (s, 1H), 6.78 (s, 1H), 6.84 (d, 2H, J=8.4 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.12 (dd, 1H, J1=8.4 Hz, J2=6.0 Hz), 7.21 (d, 3H, J=8.7 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.54 (m, 2H). MS (API-ES+): 695 (M+H).
Reaction SMILES: [C@H:1]1([NH:10][CH:11]=[CH:12][CH:13]=[C:14]([C:19]([O:21]C)=[O:20])[C:15](OC)=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].O>CO>[C@H:1]1([N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[C:15]2=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C(=CC=CN[C@@H]1CCc2ccccc21)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccn([C@@H]2CCc3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a solution of 11.0 g (1.0 eq) (R)-dimethyl 2-(3-(2,3-dihydro-1H-inden-1-ylamino)allylidene)malonate in 80 ml dry MeOH was slowly added 3.65 g (2.5 eq) NaH (60% dispersion in mineral oil) under N2 protection. The reaction was stirred at room temperature for 10 minutes and was then heated at 60° C. After 20 minutes, to the reaction mixture were added 30 ml water. The resulting mixture was heated at 60° C. for an additional 20 minutes. The solvent was removed in vacuo. The residue was diluted with 50 ml water, and extracted with hexane (2×50 ml) to remove mineral oil. Then the aqueous mixture was acidified with 2N HCl to pH 1-2 and extracted with ethyl acetate (2×100 ml). The combined organic phase was washed with 100 ml brine, dried over sodium sulfate and concentrated in vacuo to afford (R)-1-(2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid as a white solid (8.7 g, yield 93%) which was used without further purification.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=O)=[O:14])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:20])(=[O:16])=[O:14])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5]
Reactant: CC#CCOc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: -10 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
30 g (107 mmol) of the sodium salt of 4-but-2-ynyloxybenzenesulfonic acid in 120 ml of dimethylformamide are added dropwise to a solution of 28 ml (321 mmol) of oxalyl chloride in 120 ml of dichloromethane, cooled beforehand to −10° C., and then the reaction medium is stirred at ambient temperature for 18 h. 800 ml of ice are added and the medium is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. 22 g (84%) of 4-but-2-ynyloxybenzenesulfonyl chloride are obtained in the form of a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([N:29]=[CH:30][C:31]([S:35][CH2:36][CH:37]=O)=[N:32]2)=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:10][CH2:9][N:8]([CH2:37][CH2:36][S:35][C:31]2[CH:30]=[N:29][C:28]3[C:33](=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[N:32]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CNCC[C@H]1NC(=O)OCc1ccccc1
Reactant: COc1ccc2ncc(SCC=O)nc2c1
Product: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
The title compound is prepared as an off-white solid (232 mg, 70% yield) following Scheme 3 and in analogy to Example 35 using (3S,4R)-4-benzyloxycarbonylamino-piperidine-3-carboxylic acid ethyl ester (200 mg, 0.63 mmol, 1.0 eq) (prepared according to procedures described in WO2005/066176) and (7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde (158 mg, 0.63 mmol 1.0 eq) as starting materials.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].O>ClCCl>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:13]2)[N:3]=1
Reactant: CCC(=O)Cl
Reactant: Cc1nc(OC2CCNC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(C)n2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-3-nitro-6-(pyrrolidin-3-yloxy)pyridine (1.3 g) was dissolved in dichloromethane (20 ml) and triethylamine (1.57 ml) was added. The solution was cooled to 0° C. and a solution of propionyl chloride (574 mg) in dichloromethane (5 ml) was added dropwise over 5 min. The reaction mixture was allowed to come to room temperature and was stirred for another 5 min. Water (10 ml) was added. After stirring for 3 min, the phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane/methanol=98/2). Yield: 950 mg (64.9%, pale yellow oil).