Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To as solution of Example 220B (20 g, 41.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.85 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium (4.84 g, 4.19 mmol) in N,N-dimethylformamide (500 mL) was added a solution of sodium bicarbonate (7.04 g, 84 mmol) in water (40 mL) and the mixture was stirred at 80° C. for 12 hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate, water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound. MS (CI) m/z 532 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]2[O:17][CH2:18][O:19][C:14]2=[CH:13][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(OC)(O[CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:1][C:2]1[CH:16]=[C:15]2[O:17][CH2:18][O:19][C:14]2=[CH:13][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1cc2c(cc1C=CCc1ccccc1)OCO2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1C=CCc1ccccc1)OCO2

Procedure:
Preparation of final product, 2-methoxy-4,5-methylenedioxy-cinnamylbenzene (MMCB): A mixture of 19 g. of 2-hydroxy-4,5-methylenedioxy-cinnamylbenzene, 18.9 g. of dimethyl sulfate, 30.0 g. of anhydrous potassium carbonate, and 200 ml. of acetone was refluxed for 2 hrs. The mixture was then concentrated, diluted with 1% aqueous sodium hydroxide (200 ml.), and cooled. The oil which formed was extracted with ethyl ether. The ether was removed by evaporation and the residue was distilled to give MMCB (17.5 g.), b.p. 180° C at 0.25 mm. (Found: C, 75.9; H, 5.94. Calc. for C17H16O3 : C, 76.1; H, 6.01). The 100 Hz NMR spectrum of MMCB in deuterated chloroform exhibited a doublet (2 protons) at δ 3.44 (J = 6.0 Hz), a singlet (3 protons) at δ 3.74, a singlet (2 protons) at δ 5.85, a multiplet (2 protons) at δ 6.13-6.37, a singlet (1 proton) at δ 6.51, a singlet (1 proton) at δ 6.68, and a multiplet (5 protons) at δ 7.10-7.40.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:1])=[CH:6][N:5]=1
Reactant: ClI
Reactant: Nc1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1cc(Cl)ncc1I
Yield: 39.8 %

Procedure:
Iodine monochloride (0.758 g, 4.67 mmol) was added to a solution of 2-chloro-4-amino pyridine (0.500 g, 3.89 mmol) and potassium acetate (0.763 g, 7.78 mmol) in acetic acid (30 mL). The reaction mixture was heated under reflux for 4 hr. The solvent was removed in vacuo and the residue was partitioned between aqueous sodium hydrogenocarbonate (50 mL) and ethyl acetate (50 mL). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by flash silica chromatography, eluting with ethyl acetate and hexane (1/9), to give the title compound as a pink solid (0.394 g, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:37][C:38](OC(Cl)(Cl)Cl)=[O:39]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:38]([Cl:37])=[O:39])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(-c2noc(C3CNCC(c4ccc(OC(F)(F)F)cc4)C3)n2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 1.00 g (2.46 mmol) of the compound from Example 178A and 0.34 ml (248 mg, 2.46 mmol) of triethylamine were initially charged in 167 ml of dichloromethane. 0.12 ml (242 mg, 1.23 mmol) of trichloromethyl chloroformate (diphosgene) was added dropwise. The reaction mixture was stirred at RT for 16 h, washed quickly with a little ice-water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel. Yield: 944 mg (68% of theory, 83% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=2[C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:28]=[C:27]1[CH:26]([N:25]2[C:21](=[O:23])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:15]2=[O:17])[CH2:32][CH2:31][C:30](=[O:33])[NH:29]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1OC
Yield: 85 %

Procedure:
A mixture of 3-(3,4-dimethoxyphenylamino)phthalic acid (0.59 g, 1.9 mmol) and rac-α-aminoglutarimide hydrochloride (0.32 g, 1.9 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.64 g of the product at 96:4 methylene chloride-methanol, in 85% yield: mp>215-217° C.; 1H NMR (CDCl3) δ 2.15-2.19 (m, 1H), 2.74-2.96 (m, 3H), 3.88 (s, 3H), 3.91 (s, 3H), 4.97 (dd, J=11.8 Hz, J=5.1 Hz, 1H), 6.78-6.81 (m, 1H), 6.85-6.91 (m, 2H), 7.16-7.21 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.87 (s, 1H), 8.07 (s, 1H); 13C NMR (CDCl3) δ 22.8, 31.4, 49.0, 56.0, 56.2, 108.6, 110.9, 111.8, 113.2, 116.5, 118.5, 131.7, 132.4, 135.9, 145.2, 147.1, 149.8, 167.4, 168.2, 169.4, 170.8; Anal. calcd for C21H19N3O6: C, 61.61; H, 4.68; N, 10.26. Found: C, 61.47; H, 4.52; N, 10.12.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].[N:17]#[C:18][NH2:19].C1CCC(N=C=NC2CCCCC2)CC1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([NH:5][C:6]([NH:19][C:18]#[N:17])=[N:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=S)Nc1cc(F)cc(F)c1
Reactant: N#CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)NC(=Nc1cc(F)cc(F)c1)NC#N
Yield: 32.3 %

Procedure:
To a solution of 1.5 g of N-t-butyl-N'-(3,5-difluorophenyl)thiourea produced in Example A-8 in 27 ml of THF were added 0.46 g of cyanamide, 2.2 g of DCC and 0.14 ml of diisopropylethylamine. The mixture was refluxed for 24 hours and evaporated in vacuo. The residue was mixed with 100 ml of benzene and the resulting crystals were filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using a 9:1 mixture of benzene-ethyl acetate as a solvent to give 0.8 g of crude product. Recrystallization from benzene-cyclohexane mixture gave 0.5 g of the title compound as colorless needles melting at 170.0°-172.0° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl[CH2:20][O:21][CH2:22][CH2:23][Cl:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:24][CH2:23][CH2:22][O:21][CH2:20][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: ClCCOCCl
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(COCCCl)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A solution of benzyl 4-cyanopiperidine-1-carboxylate (10.0 g, 41 mmol) and 2-chloroethyl chloromethyl ether (6.3 mL, 49.2 mmol) in THF (80 mL) was cooled to −78° C. To this solution was added drop wise LiHMDS (50 mL, 50 mmol, 1N in THF) and the resulting mixture was gradually warmed to room temp over 5 h. The reaction was quenched with water and the organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (1:1 EtOAc/hexane) to give the title compound as yellow oil (11.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ: 7.33-7.31 (5H, m), 5.10 (2H, d, J=5.9 Hz), 4.21 (2H, bs), 3.79-3.76 (2H, m), 3.63-3.60 (2H, m), 3.52-3.51 (2H, m), 3.09 (2H, bs), 1.96-1.92 (2H, m), 1.55-1.51 (2H, m).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:6]=1[C:26]([OH:28])=[O:27])(O)=[O:2].FC1C=C2C(C=CC=C2[CH2:40][N:41]2C3C(=CC=CC=3)C3CC(=O)OC(=O)[C:42]2=3)=CC=1.CNC>>[CH3:40][N:41]([CH3:42])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:6]=1[C:26]([OH:28])=[O:27])=[O:2]
Reactant: O=C1Cc2c(n(Cc3cccc4ccc(F)cc34)c3ccccc23)C(=O)O1
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccccc12
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccccc12

Procedure:
3-Carboxymethyl-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (from Example 102) was converted to 9-(7-fluoro-naphthalen-1-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was converted according to Example 68.2. but using dimethyl amine to give the title compound as a white solid. MS: 403.5 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:9])[S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CNc1cncc(Br)c1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CN(c1cncc(Br)c1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
To a microwave vial equipped with a stir bar and charged with 5-bromo-N-methylpyridin-3-amine (0.250 g, 1.3 mmol) in isopropanol (3 ml), was added 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.820 g, 3.3 mmol) and pyridine (0.32 ml, 4.0 mmol) into the mixture. The vial was capped and placed into a CEM Microwave for 20 minutes at 80° C., while 50 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed mostly desired product. The mixture was diluted with DCM and saturated sodium bicarbonate solution, then extracted the organic layer with DCM (3×25 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography in a gradient of 0-5% isopropanol/DCM. The fractions with desired product were combined and concentrated in vacuo. This gave N-(5-bromopyridin-3-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.300 g, 57% yield) as an off-white crystalline solid. MS (ESI pos. ion) m/z: 396 (MH+). Calc'd exact mass for C13H10BrF3N2O2S: 395. 1H NMR (400 MHz, DMSO-d6): 3.24 (s, 3H), 7.79 (s, 2H), 8.01 (s, 3H), 8.46 (s, 1H), 8.66 (s, 1H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(P(N(C)C)(N(C)C)=O)C.[P:26](Cl)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27].Cl>CN(C1C=CN=CC=1)C.CCOCC>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[C:1](/[O:8][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)/C=C(/OP(=O)(OCC)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of ethyl benzoylacetate (10 g, 52.03 mmol) was added DMAP (699.2 mg, 5.72 mmol), HMPA (9.96 mL, 57.23 mmol), TEA (7.98 mL, 57.23 mmol). The resulting yellow solution was stirred at 0° C. for 30 minutes and then coiled to −20° C. Diethyl chlorophosphate was added dropwise to the cooled solution and a heavy precipitate began to form immediately. The yellow-orange paste was warmed to room temperature and stirred for another 4 hours. The reaction mixture was diluted with ether and acidified with 1N HCl. The ethereal extracts were washed with saturated aqueous CuSO4 to remove HMPA, dried over MgSO4, and concentrated. The residue was purified through flash column chromatography on silica gel (EtOAc:hexanes=2:3) to give 11.6 g in 68% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].Cl>>[CH:13]1([N:7]2[CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CCC(=O)N2
Yield: 64.2 %

Procedure:
A mixture of 0.25 g (0.00089 mole) of 2-chloro-9-cyclohexyl-5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.0022 g (0.0013 mole) of 4-amino-3-methoxybenzoic acid and 3 mL of 1 M hydrochloric acid was heated in a sealed vial at 100 degrees for 1.5 hours. After cooling, the solid was collected by filtration to give 0.235 g of 4-(9-cyclohexyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-28a).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:38]([O-:40])=[O:39])[N:33]=[CH:32]2>C(O)(C)C>[CH3:18][O:17][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[N:34]([C:38]([O:40][C:11]([CH3:6])([CH3:2])[CH3:10])=[O:39])[N:33]=[CH:32]4)=[N:3][C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:5]2)=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1cc2c(Cl)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Reactant: Nc1ccc2c(cnn2C(=O)[O-])c1
Solvent: CC(C)O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Temperature: 95 °C
Yield: 149.2 %

Procedure:
A mixture of 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline (0.500 g, 1.28 mmol) and 5-amino-1H-indazole-1-carboxylate (0.314 g, 1.34 mmol) in iso-propanol (30 mL) was heated at 95° C. for 30 minutes and at 95° C. for 8 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The cake was washed with iso-propanol and Et2O, triturated with CH2Cl2 and EtOAc and dried in vacuo to give tert-Butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.560 g, 0.955 mmol, 71%). MS 587 (M+1). HPLC retention time 7.21 mins.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:29][CH2:30][CH3:31]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:29][CH2:30][CH3:31]
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: CCCBr
Product: CCCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 356 and 1-bromopropane, white powdery 3-[2-(3-difluoromethoxy-4-propoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.O[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:27])[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1ccccn1
Reactant: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
1-1′-Azobis(N,N-dimethylformamide) (645 mg, 3.75 mmol) was added to a cooled solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 7) (1.42 g, 3.75 mmol), tributylphosphine (930 μl, 3.75 mmol) and 2-hydroxymethylpyridine (240 μl, 2.50 mmol) in toluene (10 ml) and the resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 15 minutes, then at room temperature for 72 hours. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane:ethyl acetate (50:50) to afford the title compound as a pale yellow oil (530 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32]O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and (2-hydroxy-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[O:6][C:7]3[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=3[CH2:9][N:10]([C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:4]=2[CH:3]=1.C(O)(=O)C.Cl>O1CCOCC1>[ClH:1].[NH2:17][CH2:16][CH2:15][C:14]([NH:13][CH2:12][C:11]([N:10]1[CH2:9][C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[O:6][C:5]2[CH:31]=[CH:32][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NCCC(=O)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
A solution of 1,1-dimethylethyl [3-[[2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]-oxazepin-10-yl)-2-oxoethyl]amino]-3-oxopropyl]carbamate (8.1 grams), glacial acetic acid (50 mL), and 6.95M HCl in dioxane (27 mL) was stirred at room temperature for 20 minutes. The reaction was evaporated in vacuo, and the residue was co-evaporated in vacuo twice with ethanol (3A; 170 mL each time). The resulting foam was crystallized from ethyl acetate/ethanol and dried in vacuo at 56° C. The yield of the title compound was 5.79 grams (85%). Analysis calculated for C18H26ClN3O3S×HCl: C, 54.56; H, 4.83; N, 10.60; Cl, 17.89. Found: C, 54.30; H, 4.79; N, 10.49; Cl, 16.77. DSC: 216°-217° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][N:31]=1>C(Cl)Cl>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[CH:4][CH:3]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(Cc2ccc(NS(=O)(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Yield: 66 %

Procedure:
D2 (500 mg, 1.64 mmol) and pyridine (1.5 mL) were combined in DCM (5 mL). 2-chloro-pyridine-5-sulfonylchloride (314 mg, 1.48 mmol) in DCM (5 mL) was added dropwise. The solution was stirred over the weekend and the solvent removed. The residue was partitioned between DCM (25 mL) and water (25 mL). The aqueous layer was re-extracted with DCM (25 mL) and the combined organic layers washed with brine (50 mL), dried and concentrated. The crude product was purified by column chromatography. Eluting with 0-50% EtOAc/petroleum ether yielded the product as a yellow foam (470.1 mg), δH (CDCl3, 400 MHz) 1.18 (3H, d), 1.46 (9H, s), 1.97 (1H, m), 2.08 (1H, m), 2.48 (1H, d), 2.68 (1H, d), 3.07 (1H, m), 3.32-3.46 (2H, AB), 3.78 (1H, d), 4.16 (1H, br.s), 7.07 (2H, d), 7.23 (2H, d), 7.39 (1H, d), 7.96 (1H, dd), 8.72 (1H, m). MS (ES+): MH+ 481.2/483.1
Reaction SMILES: [F-:1].[Na+].[CH2:3]([N:7]1[C:12](=[O:13])[N:11]([CH2:14][CH:15]([OH:18])[CH2:16]Cl)[C:9](=[O:10])[N:8]1[CH2:19][CH:20]1[O:22][CH2:21]1)[CH:4]1[O:6][CH2:5]1>CC(C)=O>[CH2:3]([N:7]1[C:12](=[O:13])[N:11]([CH2:14][CH:15]([OH:18])[CH2:16][F:1])[C:9](=[O:10])[N:8]1[CH2:19][CH:20]1[O:22][CH2:21]1)[CH:4]1[O:6][CH2:5]1
Reactant: [F-]
Reactant: O=c1n(CC(O)CCl)c(=O)n(CC2CO2)n1CC1CO1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1n(CC(O)CF)c(=O)n(CC2CO2)n1CC1CO1
Reaction time: 6 h

Procedure:
2.1 g (50 mMoles of sodium fluoride were added to a solution of 1.5 g (5 mMoles) of 1,2-diglycidyl-4-(3-chloro-2-hydroxypropyl)-urazole in 100 ml of acetone and the mixture boiled for 6 hours. After the solvent had been distilled off and the residue taken up in 50 ml of methylene chloride, followed by filtration, removal of the methylene chloride by distillation and drying in an oil pump vacuum at 40° C., 1,2-diglycidyl-4-(3-fluoro-2-hydroxypropyl)-urazole, refractive index nD20 :1.4955 (colorless liquid), was obtained in a yield of 1.5 g (100%).