Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:49]=[CH:48][C:11]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:47]=[CH:46][C:27]([C:28]([NH:30][C:31]5[CH:32]=[C:33]6[C:37](=[CH:38][CH:39]=5)[N:36]([CH2:40][C:41]([O:43]CC)=O)[CH:35]=[CH:34]6)=[O:29])=[CH:26][CH:25]=3)[CH:19]=[CH:18]4)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:50]1([NH2:53])[CH2:52][CH2:51]1>>[CH:50]1([NH:53][C:41](=[O:43])[CH2:40][N:36]2[C:37]3[C:33](=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:26]=[CH:25][C:24]([N:20]5[C:21]6[C:17](=[CH:16][C:15]([NH:14][C:12](=[O:13])[C:11]7[CH:48]=[CH:49][C:8]([N:5]8[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]8)=[CH:9][CH:10]=7)=[CH:23][CH:22]=6)[CH:18]=[CH:19]5)=[CH:47][CH:46]=4)=[CH:39][CH:38]=3)[CH:34]=[CH:35]2)[CH2:52][CH2:51]1
Reactant: CCOC(=O)Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21
Reactant: NC1CC1
Product: O=C(Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21)NC1CC1

Procedure:
Compound 969 was prepared by treatment of Compound 962 with cyclopropylamine. [M+H]+ calcd for C40H38N6O4: 667.30; found 667.31.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=[O:23])=[CH:19][CH:20]=2)[CH:15]=[N:14]1>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:22]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[N:13]([CH3:12])[N:14]=[CH:15]4)[OH:23])=[CH:3][N:4]=2)[N:7]=1
Reactant: Cn1ncc2cc(C=O)ccc21
Reactant: Clc1ccc2ncc(Br)n2n1
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (232.0 mg, 1.00 mmol) in THF (5 mL) was added EtMaBr (1M in THF, 1.50 mL, 1.50 mmol) at −10° C. After stirring at −10° C. for 1 h, 1-methyl-1H-indazole-5-carbaldehyde (240.0 mg, 1.50 mmol) was added. The mixture was allowed to warm to it slowly and stirred for 2 h. The reaction was quenched with saturated NH4Cl solution and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was washed with DCM to give the title compound as a white solid (230 mg, 70%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.21 (d, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.29 (d, 1H), 6.21 (d, 1H), 4.02 (s, 3H). LCMS (method A): [MH]+=314, tR=4.44 min.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][CH2:13]1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C@H:13]2[C:12](=[O:11])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@@H](Cc2ccc(F)cc2)C(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 39.3 %

Procedure:
Step (b) 1M LiHMDS (27.5 mL, 27.5 mmol) was added to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (6.4 g, 25 mmol) in THF (20 mL) at −78° C. The mixture was stirred for 50 minutes and then 4-fluorobenzyl bromide (3.25 mL, 26.5 mmol) in THF (2 mL) was added dropwise. The mixture was stirred for 1 hour and 40 minutes and quenched with excess saturated ammonium chloride. The mixture was warmed to ambient temperature and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate, filtered and concentrated. The solid residue was dissolved in a 3:1 hexane/methyl tert-butyl ether solvent mixture (100 mL) and slow crystallization was allowed at ambient temperature. The mixture was cooled to 0° C. and the solid was collected by filtration, washed with a 3:1 hexane/methyl tert-butyl ether solvent mixture (50 mL) and dried to give (2S,4R)-1-tert-butyl 2-ethyl 4-(4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (3.59 g, 39%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.15-7.12 (m, 2H), 7.01-6.96 (m, 2H), 4.47 (dd, J=2.0, 9.2, 1H), 4.22-4.17 (m, 2H), 3.22 (dd, J=4.4, 14.4, 1H), 2.94-2.85 (m, 1H), 2.71-2.65 (m, 1H), 2.08-1.94 (m, 2H), 1.50 (s, 9H), 1.26 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13](Br)[CH3:14])[CH:9]=2)[CH:4]=1>N1C(C)=CC(C)=CC=1C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]=[CH2:14])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(C(C)Br)ccc2c1
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: C=Cc1ccc2cc(OC)ccc2c1

Procedure:
The 2-methoxy-6-(1-bromoethyl) naphthalene prepared in Example 9 was dissolved in 8.0 grams of collidine (2,4,6-trimethylpyridine) and the mixture was refluxed for 45 minutes. The product mixture was cooled, diluted with diethylether, and washed with dilute hydrochloric acid. The ether solution was dried over anhydrous magnesium sulfate, filtered and the diethylether removed by evaporation. The structure of the resulting product was verified as 2-methoxy-6-vinylnaphthalene by 1H and 13C nuclear magnetic resonance spectroscopic analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:23]1[C:28]2=[N:29][CH:30]=[C:31]([O:33][CH3:34])[N:32]=[C:27]2[CH:26]=[CH:25][N:24]=1>>[F:20][C:5]1[C:4]([F:21])=[CH:3][C:2]([NH:1][C:23]2[C:28]3=[N:29][CH:30]=[C:31]([O:33][CH3:34])[N:32]=[C:27]3[CH:26]=[CH:25][N:24]=2)=[CH:7][C:6]=1[C@:8]1([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: COc1cnc2c(Cl)nccc2n1
Product: COc1cnc2c(Nc3cc(F)c(F)c([C@]4(C)C[C@@H](C(F)(F)F)OC(N)=N4)c3)nccc2n1

Procedure:
The titled compound was synthesized by procedure and steps analogous to those described in Method B, Example 8 above, but using (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (17i, Example 163, Method Y, step 9) and 5-chloro-2-methoxypyrido[3,4-b]pyrazine (intermediate 3) in step 2. MS m/z=469.1 [M+H]+. Calculated for C20H17F5N6O2: 468.4
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][N:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.[OH-].[Na+]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH:19][CH2:9][CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: C#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CNCCc2ccnc(Cl)c2)cc1
Temperature: 105 °C
Yield: 55.4 %

Procedure:
A mixture of 1.386 g of 2-chloro-4-ethynyl-pyridine (10.07 mmol), 2.65 ml of 4-tert-butyl-benzylamine (15.11 mmol), 0.58 ml of acetic acid (10.07 mmol) and 666 mg of sodium cyanoborohydride (95% purity, 10.07 mmol) in ethanol (12 ml) were heated to 105° C. in a sealed tube for 2 d. The reaction mixture was allowed to cool to RT, diluted with 3N NaOH solution and extracted with DCM. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. After column chromatography (heptane/EtOAc 100:0 to 0:100) 1.688 g (55%) of the title compound were isolated as a brown liquid. MS (ISP) 303.2 (M+H)+.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[NH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[N:11]([CH2:35][CH:34]=[CH2:33])[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 60 °C

Procedure:
To a solution of 5-biphenyl-4-yl-6-chloro-2-(methylsulfonyl)-1H-benzimidazole (1.72 g, 4.49 mmol) in THF (30 ml) and 1M potassium carbonate (3.10 g, 22.46 mmol) was added allyl bromide (0.6 ml, 6.89 mmol). The reaction mixture was heated to 60° C. for 20 h. Then the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and water. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica eluting with 20-40% EtOAc/hexanes afforded the desired product. LC-MS: calculated for C23H19ClN2O2S 422.09, observed m/e: 422.94 (M+H)+ (Rt 2.52/4 min).
Reaction SMILES: [C:1]1([CH2:7][C:8](C(S)C(O)=O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[NH:17]([C:19]([O:21][CH3:22])=[O:20])[NH2:18]>O>[C:1]1([CH2:7][C:8]([NH:18][NH:17][C:19]([O:21][CH3:22])=[O:20])=[S:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)NN
Reactant: O=C(O)C(S)C(=S)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NNC(=S)Cc1ccccc1
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 86.0 g of 2-(2-phenyl-1-thioxoethyl)thioglycolic acid, 195 ml of 2N sodium hydroxide and 100 ml of water was added dropwise to a suspension of 50 g of methyl hydrazinocarboxylate in 200 ml of water with vigorous stirring. Stirring was continued overnight, then the mixture was extracted twice with ether. The extracts were combined, washed successively with 5% aqueous sodium bicarbonate (twice), water and saturated aqueous sodium chloride, dried and concentrated in vacuo. The dark orange oil was purified by percolation through a bed of hydrous magnesium silicate with dichloromethane. The resulting pale yellow oil was chromatographed on a 70×850 mm dry column of silica gel, eluting with dichloromethane. The resulting oil was crystallized from toluene-hexane, giving 42.6 g of the desired compound as yellow crystals, mp 93.5-94° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 3.79 (s, 3H, OCH3); 4.11 (s, 2H, CH3CS); 7.33 (bs, 5H, C6H5); 8.65 (bs, 1H, NH); 9.55 (bs, 1H, NH).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]C2C(O)=CC=CC=2)=[CH:3][CH:2]=1.[C:15]1([CH2:21][C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]=[O:26])[C:23]=2[OH:30])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:4]1([CH2:7][O:30][C:23]2[C:22]([CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=[O:26])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=Cc1cccc(Cc2ccccc2)c1O
Reactant: Oc1ccccc1Cc1ccccc1
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(Cc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Yield: 71 %

Procedure:
Using the method of Tramposch, Kung and Blau (J. Med. Chem. (1983) 26, 121), 2-hydroxydiphenylmethane was converted to 3-(phenylmethyl)salicylaldehyde in 56% yield: NMR (CDCl3) 11.35 (s, 1H), 9.35 (s, 1H), 7.45-6.85 (m, 8H), 4.00 (s, 2H); Mass spec (CI) 213. This hydroxyaldehyde (31.3 g, 0.147 mole) was treated with benzyl bromide (25.2 g, 0.147 mole) and potassium carbonate (22.1 g, 0.16 mole) in N,N-dimethylformamide (180 mL) at 100° overnight. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Distillation of the residue (170°-185°, 0.1 torr) provided the title material as a pale yellow viscous oil in 71% yield. NMR (CDCl3) 10.3 (s, 1H), 7.8-7.1 (m, 13H), 4.9 (s, 2H), 4.05 (s, 2H).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH3:6]>>[CH3:3][C:2](=[CH:1][N:6]=[CH:1][CH:2]([CH3:4])[CH3:3])[CH3:4]
Reactant: CC(C)C=O
Reactant: N
Product: CC(C)=CN=CC(C)C

Procedure:
When isobutyraldehyde was reacted under conditions similar as described in Example I, above, for the preparation of dihydrothiazoles from ketones, no incorporation of sulfur occurred. However with a variation in the reaction, secondary aldehydes could be made to yield dihydrothiazoles in excellent yield. The reaction of isobutyraldehyde with ammonia yielded, via an intermediate, 2,6-dimethyl-4-azahepta-2,4-diene.
Reaction SMILES: [C:1]([CH:3]=[CH:4][NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])C(OCC)=O)#[N:2].C(O)(=O)C>C(O)C.C([O-])C.[Na+]>[NH2:2][C:1]1[CH:3]=[CH:4][NH:5][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(NC=CC#N)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.4 %

Procedure:
Into a 1000-mL round-bottom flask was placed a solution of diethyl 2-(2-cyanovinylamino)malonate (30 g, 119.3 mmol, 1.00 equiv, 90%) in ethanol (420 mL) and sodium ethanolate (80 mL, 21%). The resulting solution was stirred for 3 days at room temperature. After the addition of acetic acid (15 ml), the resulting mixture was concentrated under vacuum, dissolved in 200 mL of dichloromethane, washed with 2×100 mL of saturated aqueous sodium bicarbonate and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was dried in HV to afford 10 g (49%) of ethyl 3-amino-1H-pyrrole-2-carboxylate as an orange syrup.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)co1
Solvent: CCCCO
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)co1
Temperature: 160 °C

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide (160 mg, 0.472 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (378 mg, 1.89 mmol) in n-BuOH (3 mL) was stirred at 160° C. in a sealed tube. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by C-18 reverse phase flash chromatography (Biotage Flash 25 M+) on SP4 unit eluting with 10-85% CH3CN/water gradient (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-methyloxazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid. This material was treated with neat TFA (3 mL), and after 30 minutes the mixture was concentrated in vacuo. The residue obtained was dissolved in few drops of CH2Cl2 and treated with 2M HCl in ether (3 mL). The solid formed was filtered, washed with additional Et2O and dried under high vacuum to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide hydrochloride (23 mg, 12% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.85 (s, 1H), 10.41 (s, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 8.27 (br s, 3H), 8.02 (s, 1H), 4.01-3.99 (m, 1H), 3.69-3.63 (m, 1H), 3.60-3.52 (m, 1H), 3.36-3.29 (m, 1H), 3.06-2.99 (m, 1H), 2.58 (s, 3H), 2.34-2.25 (m, 2H), 1.89-1.82 (m, 1H), 1.59-1.51 (m, 1H); LCMS (APCI+) m/z 419, 421 (M+H)+, Retention time=2.44 minutes (Method 2).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[C:24]1([CH2:30][CH:31]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:31]([CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=CCc1ccccc1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cc2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in dimethylformamide (3 mL) was added phenylacetaldehyde (101 mg, 0.840 mmol) and oxone (258 mg, 0.420 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (110 mg, 42% yield) as light brown amorphous mass.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](SC)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:20].ClC1C=C(C=CC=1)C(OO)=O.[CH:32]([NH2:35])([CH3:34])[CH3:33]>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:35][CH:32]([CH3:34])[CH3:33])[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:20]
Reactant: CC(C)N
Reactant: CSc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)Nc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 8-bromo-2-(methylthio)-3-(pyridin-2-yl)quinazolin-4(3H)-one (179 mg, 0.514 mmol, 415c) in DCM (5.1 mL) was set stirring and 3-chloroperoxybenzoic acid (127 mg, 0.565 mmol, 77% max.; Sigma Aldrich) was added. The mixture was stirred for 4 h to give a mixture of sulfone and sulfoxide. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow residue. The residue and isopropylamine (1.7 mL, 19.73 mmol) was set stirring at 80° C. for 30 min. The reaction was cooled to RT and diluted with water. The mixture was extracted with DCM and dried over Na2SO4. Silica was added, and the material was adsorbed under reduced pressure. It was purified on 12 g SiO2 (eluent: 0-100% EtOAc/hexanes over 25 min, RediSep Gold). The product fractions were combined and concentrated under reduced pressure to give 8-bromo-2-(isopropylamino)-3-(pyridin-2-yl)quinazolin-4(3H)-one (71 mg, 30% for 2 steps). 1H NMR (400 MHz, DMSO-d6) ppm 8.69 (1H, dd, J=4.79, 1.08 Hz) 8.08 (1H, td, J=7.73, 1.76 Hz) 7.97 (1H, dd, J=7.63, 1.37 Hz) 7.88 (1H, dd, J=7.92, 1.47 Hz) 7.55-7.63 (2H, m) 7.03 (1H, t, J=7.73 Hz) 5.90 (1H, d, J=7.63 Hz) 1.15 (6H, d, J=6.65 Hz). m/z (ESI, +ve) 360.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.CN(C)[CH:22]=[O:23].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[CH:22]=[O:23])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CN(C)C=O
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 12.96 g (60 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 300 mL THF under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 52.35 ml, (123 mmol) 2.35M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added 4.64 ml, (60 mmol) of N,N-dimethylformamide dropwise. The reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 5.72 g of the title compound as a white solid, m.p. 101.5°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>OS(O)(=O)=O>[Br:19][C:9]1[C:2]([F:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: COc1cc(F)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: COc1cc(F)c(Br)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-2-methoxybenzonitrile (35 g, 0.23 mol) in 300 mL of concentrated H2SO4 was added NBS (42 g, 0.23 mol) portionwise at −10° C. and the reaction was stirred at r.t. for 2 hours. Then the reaction was poured into 2 L of ice portionwise, and the solid precipitated out was filtered. The filter cake was washed with water, then the solid was dried in vacuo to give 5-bromo-4-fluoro-2-methoxybenzonitrile.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:51]([OH:59])(=[S:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:58][C:51](=[O:59])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cnn(C)c1
Reactant: OC(=S)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1cnn(C)c1
Reaction time: 0.25 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-{(1-methylpyrazol-4-yl)methyl)pyrrolidine (15.3 g) and triphenylphosphine (19.67 g) in tetrahydrofuran (180 ml) was added diethyl azodicarboxylate (13.06 g) at -30° C. After 15 minutes, thiobenzoic acid (9.5 ml) was added thereto. The mixture was warmed up to 0°~5° C. over 25 minutes and stirred for 2 hours. After evaporation of tetrahydrofuran, the resulting residue was dissolved in ethyl acetate (500 ml). The organic layer was washed with saturated sodium bicarbonate solution (×3), water and brine, dried over magnesium sulfate and evaporated under reduced pressure. After storing the residue overnight in an ice box, a precipitate had appeared. To the precipitate was added a solution of diisopropyl ether (IPE)--diethyl ether (1:1, 100 ml) and the solid was removed by filtration. The filtrate was evaporated and the residue was column chromatographed on silica gel (1.1 kg, eluting with AcOEt-IPE=2:3 to 1:1) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-{(1-methylpyrazol-4-yl)methyl}pyrrolidine (21.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([S:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([S:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)Sc1cccnc1-c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1cccnc1-c1ccc(C#N)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate (0.137 g, 0.42 mmol), aqueous sodium hydroxide solution (1M, 1 mL) and methanol (2 mL) was stirred at 60° C. for 12 hours. The reaction mixture was concentrated to remove methanol, acidified and filtered to obtain 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoic acid as a white powder (0.121 g, 96%).