Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:35])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]=2[NH:16][C:15]1=[O:34])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][C:39]=1[O:48][CH3:49].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:49][O:48][C:39]1[CH:40]=[CH:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]=1[CH2:37][N:16]1[C:15](=[O:34])[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:35])[C@H:20]([CH3:21])[N:19]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]1=2
Reactant: COc1ccc2ccccc2c1CCl
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To a room temperature solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (prepared as in Example RK-1, Step 3, 75 mg, 154 μmol) in N,N-dimethylformamide (500 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (38 mg, 184 μmol), cesium carbonate (65 mg, 200 μmol), and sodium iodide (30 mg, 200 μmol). The reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL) the aqueous layer was then extracted with ethyl acetate (2×20 mL) and the organic layers combined and then washed with a saturated aqueous sodium chloride solution (30 mL), dried over magnesium sulfate, filtered, and the filterate concentrated in vacuo. The crude material was purified by flash chromatography to afford tert-butyl(S)-1-((3S,4S)-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (53 mg, 52%) as a light yellow foam: LC-MS m/z 681 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21]([OH:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:23][CH2:21][CH3:22])[CH:9]=1)[C:5]#[N:6]
Reactant: CCO
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCOc1cc(Br)cc(C#N)c1
Yield: 44 %

Procedure:
In analogy to the procedure described in WO2007060448, the reaction of 3-bromo-5-fluorobenzonitrile with ethanol using sodium bis(trimethylsilyl)amide as the base yielded the title compound as a light brown oil (yield: 44% of theory).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][C:3]#[CH:4]>C(Cl)Cl>[CH3:17][O:16][C:14]([C:12]1[CH:11]=[CH:10][C:8]2[CH:9]=[C:5]([CH2:1][CH2:2][C:3]3[O:6][C:7]4[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:8]=4[CH:4]=3)[O:6][C:7]=2[CH:13]=1)=[O:15]
Reactant: C#CCCc1cc2ccc(C(=O)OC)cc2o1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(CCc3cc4ccc(C(=O)OC)cc4o3)oc2c1

Procedure:
Following the procedure described above for 95, 101 was prepared from 94 to 100 as a white solid (0.6 g, 24%): mp 175-177° C. (CH2Cl2). 1H NMR (DMSO-d6) δ8.04 (b, 2H), 7.83 (dd, J=8.2, 1.1 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 6.83 (s, 2H), 3.87 (s, 6H), 3.33 (s, 4H). HPLC (method B) tR 9.16 min (100.00 area %). Anal. (C22H18O6) C, H.
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([NH:41][C:20](=[O:22])[C@H:16]([CH:17]([CH3:18])[CH3:19])[NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH3:40])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(C)N)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: COc1ccc(C(C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 217.1 %

Procedure:
2.3 g (0.023 mol) of N-methylpiperidine are added to 5.0 g of t-butoxycarbonyl-L-valine (0.023 mol), dissolved in 50 ml of CH2Cl2, at -20° C. 3.2 g (0.023 mol) of isobutyl chloroformate are then rapidly added dropwise at -20° C., the mixture is subsequently stirred at the same temperature for 10 minutes and cooled to -60° C. and 3.5 g (0.023 mol) of 4-methoxy-1-phenylethylamine are allowed to run in, the temperature being kept below -15° C. After 2 hours at -15° C., the mixture is subsequently stirred at room temperature for 15 hours, the solid is filtered off and rinsed with CH2Cl2, the filtrate is concentrated, the residue is introduced into water, the mixture is extracted twice with ethyl acetate and the combined ethyl acetate phases are washed with NaHCO3 solution and water, dried and concentrated. 17.5 g (85% of theory) of N-(t-butoxycarbonyl)-L-valine 4-methoxy-1-phenylethylamide of melting point 126°-127° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:32]N1C(=O)CCC1=O>>[Br:32][CH2:25][C:13]1[C:12]([C:26](=[O:31])[CH2:27][CH:28]([CH3:29])[CH3:30])=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=1
Reactant: COc1ccc(-c2c(C(=O)CC(C)C)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(-c2c(C(=O)CC(C)C)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Reference Example 5, 4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxy-2-methylquinoline was brominated with N-bromo-succinimide (NBS) to give 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxyquinoline. This compound was recrystallized from ethyl acetate - hexane to give colorless prisms. mp. 159°-161° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2cccnc2)c1F
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4cccnc4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid as described in Example 1 to give 2-[3-(2-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 1.56 (6H, s), 7.65 (1H, dd, J 8 and 8), 7.79-7.83 (1H, m), 7.85-7.87 (2H, m), 7.92-7.97 (1H, m), 8.48 (1H, d, J 7), 8.55 (1H, s), 8.83 (1H, dd, J 5 and 1), 9.10 (1H, s), 9.29 (1H, dd, J 7 and 3); m/z (ES+) 349 (M++H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][C:28]=1[C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[CH:32]=[C:33]([O:36][CH2:37][O:38][CH3:39])[CH:34]=[CH:35][C:27]=4[F:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COCOc1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCOc1ccc(F)c(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Reaction time: 1.5 h

Procedure:
To a solution of 4.5 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) in 60 ml of DCM a solution of 2.4 g 2-fluoro-5-(methoxymethoxy)benzoic acid 20 ml of DCM, 1.7 ml TEA, 1.7 g HOBt and 2.4 g EDCi*HCl are added. The reaction mixture is stirred for 90 min until the reaction is complete according to TLC analysis. The reaction mixture is quenched with 1 M aqueous hydrochloric acid, the phases are separated and the organic phase is washed with 1 M aqueous hydrochloric acid again, with water, twice with 1M aqueous sodium carbonate solution and with brine. The organic phase is dried over MgSO4, and the solvent is removed under reduced pressure resulting in a crude product, which is purified by crystallization from diethyl ether to yield 5-(3,4-dimethoxyphenyl)-2-(1-{[2-fluoro-5-(methoxymethoxy)phenyl]carbonyl}piperidin-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1.C([O-])([O-])=O.[Cs+].[Cs+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:40]4[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=2)=[CH:26][CH:27]=1)(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Cs+]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCS(=O)(=O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and thiomorpholine-1,1-dioxide and replacing Cs2CO3, with K3PO4. MS (ES+): m/z 683.25 (100) [MH+]; HPLC: tR=0.98 min (UPLC, purity).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:17][CH2:18][O:11][C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:12]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.5 %

Procedure:
To a solution of (4R)-(tert-Butoxycarbonyl)-4-hydroxy-L-proline (26) (0.92 g, 4.0 mmol) in dry CH2Cl2 (30 ml) was added ethanol (1 ml, 21 mmol). To the reaction was added DCC (1.64 g, 8.0 mmol) and DMAP (cat) and the reaction mixture was, stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (10:1)to give 1.8 g oil as desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23]C)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=O)C=1.ClC(Cl)(Cl)C([N:42]=C=O)=O.[N-]=C=O>CO>[NH2:42][C:9]1[C:8]2[N:17]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [N-]=C=O
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(=O)OC
Reaction time: 72 h
Yield: 103.8 %

Procedure:
A modification of the methods described in Part B of Example 60 was used to treat ethyl 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (11.0 g, 31 mmol) with mCPBA (13.6 g of 77% pure material), followed by trichloroacetyl isocyanate (4.4 mL, 37 mmol). The reaction with the isocyanate was stirred for 1.5 hours before the addition of additional trichloroacetyl isocyanate (4.4 mL) and stirring for three days. Additional trichloroacetyl isocyanate (0.5 mL) was added, and the reaction was stirred for four hours. After the addition of methanol (50 mL), the solution was stirred overnight, and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (150 mL), and the solution was washed with saturated aqueous sodium bicarbonate (2×35 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL ammonium hydroxide per liter of eluent) to provide 11.4 g of methyl 3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as a semi-solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[NH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([Cl:23])=[N:15][N:14]=1)[NH2:12].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[N:14]2[N:15]=[C:16]([Cl:23])[C:17]3[C:22]([C:13]2=[N:11][N:12]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=C(Cl)c1ccccc1Br
Reactant: NNc1nnc(Cl)c2ccccc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccccc3Br)nnc2c2ccccc12
Yield: 60 %

Procedure:
A solution of 2-bromobenzoyl chloride (0.12 mole) in dioxane (50 ml) is added to a mixture of 1-hydrazino-4-chlorophthalazine (0.1 mole), triethylamine (0.12 mole) and dioxane (200 ml). The reaction mixture is refluxed for five hours then the solvent is evaporated off and the obtained residue is washed with a small amount of water and crystallized from methanol giving the compound of the title in 60% yield. M.p. 203°-04° C.
Reaction SMILES: COC1C=CC(C[N:8]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:19][CH2:18][O:17][C:16]=3[CH:33]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:33]=[C:12]([S:9]([NH:8][C:34]4[S:35][CH:36]=[CH:37][N:38]=4)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]2=3)[CH:32]=[N:31][CH:30]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2-c2cncnc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccccc1-c1cncnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of N-(4-methoxybenzyl)-4-(2-(pyrimidin-5-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (250 mg, 0.437 mmol) in DCM (5 mL) was added TFA (2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (8 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material (69.61% by LCMS) that was purified by prep purification to obtain 4-(2-(pyrimidin-5-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (60 mg, 30.4%) as white solid. 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 9.06 (s, 1H), 8.83 (s, 2H), 7.61 (td, J=6.9, 2.0 Hz, 2H), 7.58-7.48 (m, 2H), 7.21 (d, J=4.7 Hz, 1H), 7.01 (td, J=4.8, 4.2, 1.8 Hz, 2H), 6.77 (d, J=4.7 Hz, 1H), 6.21 (d, J=9.0 Hz, 1H), 4.30 (dt, J=11.1, 3.2 Hz, 1H), 4.03 (ddd, J=10.9, 8.6, 2.7 Hz, 1H), 3.76 (ddd, J=11.3, 8.3, 3.0 Hz, 1H), 3.44 (dt, J=12.3, 3.1 Hz, 1H); MS (ESI, positive ion) m/z: 452.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[N:4]1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[N:4]1[CH3:13])(=[O:24])=[O:23]
Reactant: CN1C(=O)[C@@H]2CCCN2C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)[C@@H]2CCCN2C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 74.8 %

Procedure:
(3S,8aS)-3-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-α]pyrazin-1(2H)-one (505 mg, 2.74 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.8 mL, 5.75 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.45 mL, 5.81 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford [(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-α]pyrazin-3-yl]methyl methanesulfonate as an orange oil (538 mg, 2.05 mmol, 75% yield). 4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (469 mg, 1.20 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (828 mg, 6.00 mmol) was added followed by [(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-α]pyrazin-3-yl]methyl methanesulfonate (538 mg, 2.05 mmol) in dimethylformamide (1 mL). The mixture was stirred at 70° C. for 34 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography (6-8% methanol in dichloromethane) to afford a yellow foam (300 mg, 0.577 mmol, 48% yield). The yellow foam (100 mg) was purified further by column chromatography (ethyl acetate-ethanol 1:1) to afford (3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-α]pyrazin-1(2H)-one as a yellow solid (60 mg). 1H NMR (400 MHz, CDCl3): 8.71 (s, 1H), 8.52 (dd, 1H), 7.36-7.32 (m, 2H), 7.01 (s, 1H), 4.49 (dd, 1H), 4.34 (dd, 1H), 4.03 (s, 3H), 3.90-3.84 (m, 1H), 3.47 (t, 1H), 3.13 (s, 3H), 3.05 (dd, 1H), 2.95 (dd, 1H), 2.93-2.83 (m, 2H), 2.29-2.19 (m, 1H), 2.03-1.84 (m, 2H), 1.83-1.70 (m, 1H); MS (EI) for C24H24N5O3FCl2: 520 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[N:29][C:30]=1[F:31]>O>[Cl:24][C:25]1[C:30]([F:31])=[N:29][CH:28]=[C:27]([O:32][CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[CH:26]=1
Reactant: BrCCCOC1CCCCO1
Reactant: Oc1cnc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1ncc(OCCCOC2CCCCO2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
2-(3-Bromopropoxy)tetrahydro-2H-pyran (12.93 g, 57.9 mmol) and cesium carbonate (39.5 g, 121.0 mmol) were added to an N,N-dimethylacetamide solution (80 ml) of 5-chloro-6-fluoropyridin-3-ol (8.14 g, 55.2 mmol), and stirred overnight under a nitrogen atmosphere at 100° C. The reaction solution was cooled with ice, water was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Moritex NH, hexane:ethyl acetate=18:1 to 11:1) to obtain 3-chloro-2-fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (10.84 g, yield: 68%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([CH3:34])[CH2:29][CH2:28][CH:27]([CH:30]([CH3:32])[CH3:31])[CH:26](O)[CH2:25]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:30]([CH:27]1[CH2:28][CH2:29][CH:24]([CH3:34])[CH2:25][CH:26]1[O:22][C:21]([CH:9]1[CH2:10][C:11](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2cccc(F)c2)CC1C(=O)O
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(OC(=O)C2CC(=Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 31.3 %

Procedure:
To a solution of 4-(3-Fluoro-benzylidene)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.68 g, 8.35 mmol), 1R,2S,5R(−) menthol (1.31 g, 8.35 mmol) was added followed by dimethylaminopyridine (1.02 g, 8.35 mmol). The mixture was cooled to 0° C. and dicyclohexylcarbodiimide (1.89 g, 9.19 mmol) in dichloromethane (10 ml) was added in one portion. The mixture was warmed to room temperature stirred for 18 h. The mixture was filtered and the filtrate was washed with 1N hydrochloric acid (30 ml), sat. sodium hydrogen carbonate (30 ml) and water (30 ml). The organics were dried over magnesium sulphate and the solvent was removed by evaporation under reduced pressure. Purification by flashmaster column chromatography eluting with heptane:ethyl acetate (12:1) yielded the title compound (1.20 g, 31%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(NC3C=CC(CC)=CC=3)=O)=[CH:11][CH:10]=2)[CH:3]=1.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:32][CH:33]=3)=[O:39])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reaction time: 3 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), 4-tert-butyl-phenyl-isocyanate, and DMF as the solvent. The reaction mixture is stirred for 3 h. The title compound is obtained as a white solid: ES-MS: 348.0 [M+H]+; single peak at tR=6.94 min (System 2).