Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:7])[C:4]([O-:6])=[O:5].[Li+].Cl.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: C=C(CO)C(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: [Li+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
To lithium 2-(hydroxymethyl)prop-2-enoate (926 mg, 8.57 mmol) was added DMF (17.0 mL), HCl (1.07 mL, 4 M in dioxanes, 4.28 mmol) and imidazole (700 mg, 10.3 mmol), followed by TBS-Cl (2.84 g, 18.9 mmol) at 25° C. The reaction was stirred overnight, then quenched by pouring into a separatory funnel containing water. The aqueous layer was brought to pH˜3 with 1 N HCl and was extracted with ethyl acetate (×3). The organic layers were combined and dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography using MPLC using 5-80% EtOAc/hexanes. The monoprotected product was collected and concentrated in vacuo to afford a clear oil. 1H NMR (600 MHz, DMSO-D6) δ 12.67 (s, 1H), 6.13 (s, 1H), 5.80 (s, 1H), 4.31 (s, 2H), 0.92 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[O:11][C:10]=2[CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[O:11][C:10]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccncc2)cc1C(O)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccncc2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methanol (0.9 g) in toluene (10 mL) was added thionyl chloride (0.7 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (0.9 g, 100%) as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27].[ClH:29]>CO.O1CCOCC1>[ClH:29].[ClH:29].[N+:26]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:25]=2)[CH:4]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of 1,1-dimethylethy 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.5 g, 9.1 mmol, example 26, step 1) in methanol (75 mL) and 4N hydrogen chloride in dioxane (11 mL) was stirred at 50° C. for 1.5 h and then concentrated. The resulting residue was triturated with a 10% methanol in diethyl ether solution (50 mL) to provide 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (3.1 g, 95%) as a red solid. 1H NMR (400 MHz, d6-DMSO) δ 9.76 (bs, 2H), 8.80 (d, 1H), 8.60 (s, 1H), 7.90 (s, 1H), 7.73 (dd, 1H), 7.16 (d, 1H), 4.39 (bs, 2H), 4.25 (bs, 2H), 3.48 (bs, 2H); MS (EI) for C14H14N4O3: 287 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1S2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCCCC3)ccc1S2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 20 g of 2,7-bis(5-chlorovaleryl)thioxanthene, 2 g of potassium iodide, 70 ml of piperidine and 150 ml of tetrahydrofuran was heated in a Paar bomb at 100°C. with stirring for 48 hours. Upon cooling, the solvent was evaporated, and the remaining material was poured into water then filtered. The residue was recrystallized several times from heptane to give the desired product. M.P. 98.5°-99.5°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.[H][H]>CO.[Pd]>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[NH2:17][C:16]1[CH:15]=[CH:14][C:4]([O:5][CH2:6][C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Yield: 45.8 %

Procedure:
To a solution of the product from step (a) (4.18 g) in methanol (250 ml) under argon was added p-toluenesulphonic acid monohydrate (2.99 g) followed by 10% Pd on C (1.8 g). The argon was replaced by hydrogen and the reaction mixture was stirred under a blanket of hydrogen for 6 hours. The catalyst was filtered off through a pad of diatomaceous earth and washed with methanol. The blue-coloured filtrate and washings were evaporated to near dryness and excess ether was added. On storage overnight at -10° C. a solid crystallised which was collected, washed with ether and dried to give t-butyl 4-amino-3-methylphenoxyacetate, p-toluenesulphonate salt (2.93 g) as an off-white solid: NMR Spectrum (DMSO-d6) 1.42 (9H, s), 2.28 (3H, s), 2.30 (3H, s), 4.63 (2H, s), 6.82 (1H, dd), 6.88 (1H, d), 7.12 (2H, d), 7.24 (1H, d), 7.48 (2H, d), 9.50 (3H, br s); Mass Spectrum m/Z 260 (M+Na)+.
Reaction SMILES: [CH2:1]([NH:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:11]([OH:12])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:24])[CH3:21]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCCCCCCCCNO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCN(O)C(=O)N(CC)CC
Reaction time: 2 h

Procedure:
To a stirred solution of N-decylhydroxylamine (2.60 g, 15.0 mmol) and triethylamine (2.3 ml) in tetrahydrofuran (hereinafter THF) (30 ml) at 0° C. was added dropwise N,N-diethylcarbamyl chloride (1.92 ml). After two hours, 4-(dimethylamino)pyridine (1.3 g) was added. After 18 hours, the reaction mixture was quenched with 1N hydrochloric acid (hereinafter HCl), extracted with hexane, and the organic solution was dried over MgSO4, filtered and evaporated. Trituration of the residue with hexane at -30° C. gave the title compound as a while solid (3.1 g, mp 35°-37° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:6]
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 1.1 g, 5.00 mmol) was dissolved in DCM (10 mL) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) added. The mixture was cooled in an ice/water bath and 4-(2-aminoethyl)morpholine (Aldrich; 0.66 mL, 5.00 mmol) in DCM (5 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. The reaction mixture was washed with brine, 2N NaOH, dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeoH/DCM) gave the title compound as a yellow solid. (1.2 g, 76%)
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[CH3:9][CH2:10][O:11][C:12]([C:14]1[N:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:16]2[C:21]([CH:22]=1)=[C:20](OCC1C=CC=CC=1)[CH:19]=[CH:18][CH:17]=2)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1>[CH3:9][CH2:10][O:11][C:12]([C:14]1[N:15]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:16]2[C:21]([CH:22]=1)=[C:20]([O:8][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1)[CH:19]=[CH:18][CH:17]=2)=[O:13]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Reactant: Cc1nc(CO)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(OCc3csc(C)n3)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
(2-Methyl-thiazol-4-yl)-methanol (168, 670 mg, 5.2 mmol) is dissolved in 12 ml of dry THF under argon, followed by addition of 4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (102, see example 42, 1.58 g, 5.2 mmol), triphenylphosphine (1.63 g, 6.2 mmol).) and the solution is cooled to 0° C. A 40% solution of ethyl azadicarboxylate in toluene (2.7 ml, 6.2 mmol) is added dropwise and the mixture is stirred for 2.5 h at 0° C. The solvents are removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with sodium hydrogencarbonate solution and brine. The organic layers are dried over sodium sulphate, filtrated and evaporated. The crude product is purified by flash chromatography (silica gel, ethyl acetate/hexanes 3:7)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1.[Cl:25]Cl>Cl.C(O)=O.ClCCCl>[Cl:25][C:18]1[C:13]2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=1
Reactant: ClCl
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: Cl
Solvent: ClCCCl
Solvent: O=CO
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 160 g (0.49 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one in 400 ml of concentrated hydrochloric acid and 400 ml of formic acid is treated while stirring with a solution of 46 g of chlorine gas in 400 ml of 1,2-dichloroethane. The reaction mixture, which consists of two phases, is stirred at room temperature, whereby after 3 days a further 25 g of chlorine gas in 200 ml of 1,2-dichloroethane are added and after 5 days a further 5 g of chlorine gas in 40 ml of 1,2-dichloroethane are added. After 7 days, the mixture is concentrated, treated with ice-water, made alkaline with aqueous ammonia and extracted four times with methylene chloride. The organic extract is concentrated and treated with 600 ml of isopropanol. Subsequently, the residual methylene chloride is removed on a steam-bath and the product is left to crystallise. There is obtained 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 174°-175°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=2)=[N:32][C:31]=1[C:42](O)=[O:43])=O)(C)(C)C>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=2)=[N:32][C:31]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Product: Nc1sc(-c2ncccc2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Yield: 55 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (50 mg, 55%). 1H NMR (500 MHz, DMSO) δ 9.40 (s, 1H), 8.44 (d, J=4.6 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.86 (dd, J=25.8, 14.5 Hz, 3H), 7.58-7.40 (m, 1H), 7.13 (d, J=5.2 Hz, 1H), 3.09 (d, J=9.1 Hz, 1H), 3.00 (d, J=12.6 Hz, 2H), 2.59 (dd, J=26.2, 15.4 Hz, 1H), 2.37 (t, J=10.1 Hz, 1H), 1.90 (s, 1H), 1.78 (d, J=15.8 Hz, 2H), 1.14 (d, J=8.7 Hz, 1H). ESIMS m/z=414.1 (M+1).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CCN(CC)CC>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Yield: 65.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.092 g, 0.28 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.051 g, 0.31 mmol) in Et3N (½ mL) were reacted according to GP15 to give the title compound (108LM38-35) (0.068 g, 64%). 1H NMR (CDCl3) δ 7.32 (d, J=6.7 Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=7.2 Hz, J=10.8 Hz, CH2), 4.12-4.00 (m, 2H), 3.16 (bs, 1H), 3.07 (bs, 1H), 2.33 (dd, J=6.1 Hz, J=2.1 Hz, 1H), 2.12 (t, J=4.7 Hz, 1H), 2.01-1.78 (m, 2H), 1.58-1.40 (m, 5H), 1.38-1.13 (m, 9H), 0.92-0.84 (m, 6H); 13C NMR (CDCl3) δ 164.9, 145.7, 128.9, 123.7, 122.7, 117.1, 116.2, 67.9, 61.8, 60.0, 58.1, 45.4, 38.7, 38.6, 37.1, 31.6, 29.4, 28.2, 27.4, 26.5, 23.1, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=371.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[H-].[Na+].[CH2:29](Br)[CH3:30]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH2:29][CH3:30])[C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(-c2c(Cl)cccc2Cl)nn(-c2ccc(C(=O)OC)c(OC)c2)c1=O
Reaction time: 0.42 h
Yield: 37.9 %

Procedure:
To a solution of methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol) in dry DMF (3 mL) was added NaH (0.012 g, 0.30 mmol) at 0° C. and the reaction mixture was stirred for 20-30 minutes. Ethyl bromide (0.028 g, 0.25 mmol) was added and the reaction mixture was further stirred at 60° C. for 5-6 h. The reaction mass was quenched with water and extracted in ethyl acetate. The organic layer was dried and concentrated to afford 0.040 g of the crude product which was further purified by column chromatography in basic alumina eluting with 0.5-1.0% methanol:DCM to afford 0.040 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (t, 3H), 3.54-3.56 (m, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 7.65 (d, J=8.4 Hz, 1H), 7.77 (m, 4H), 7.84 (d, J=8.4 Hz, 1H); MS (m/z): 421.95 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]2.[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:46]5[CH2:50][CH2:49][CH2:48][CH2:47]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C1CCNC1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 187.5 %

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.040 mmole) in DMSO (2 mL) was added pyrrolidine (0.143 g, 0.16 mL, 2.00 mmole) and the reaction was stirred at 85° C. for 4 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH) to give 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine (0.042 g, 0.075 mmole, 19%). MS 557 (M+1). HPLC retention time 5.34 mins.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([CH3:38])[C:9]=2[CH:39]=1)(=[O:3])[CH3:2].O1CCCC1.[OH-].[Li+]>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([CH3:38])[C:9]=2[CH:39]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NC(C)=O)cc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a mixture of ethyl 3-[{[4-({[5-(acetylamino)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}(methyl)amino]-propanoate (366 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr. 1N Lithium hydroxide aqueous solution (1.00 mL) was additionally added, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (292 mg, 84%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:17][C:18]([CH:24]1[CH2:26][CH2:25]1)([CH3:23])[CH2:19][C:20]([NH2:22])=[O:21]>>[NH2:22][C:20](=[O:21])[CH2:19][C:18]([NH:17][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH2:15][F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH:24]1[CH2:26][CH2:25]1)[CH3:23]
Reactant: CC(N)(CC(N)=O)C1CC1
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCCF)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)pyridine-2-carboxylic acid (example 146b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (65 mg, 56%) as; MS (ESI, m/z): 350.3 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl[CH2:17][CH:18]([OH:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:20][CH:18]([CH3:19])[CH2:17][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(O)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
18.30 g (172.6 mmol) of sodium carbonate are added to a solution of 7.03 g (57.5 mmol) of p-hydroxybenzaldehyde and 6.80 g (71.9 mmol) of 1-chloro-2-propanol (technical grade, about 70% pure, isomer mixture with 2-chloro-1-propanol) in 125 ml of dry DMF, and the mixture is stirred at +130° C. for 20 h. After cooling to RT, 100 ml of saturated sodium bicarbonate solution are added and the mixture is extracted with ethyl acetate (three times, 100 ml each). The combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane/ethyl acetate 5:1→2:1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2].[CH2:32]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:32])[CH:15]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COc4ccccc4)C3)cc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(COc4ccccc4)C3)cc21

Procedure:
A 200 mg portion of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(phenoxymethyl)-1-piperazinyl]-3-quinolinecarboxylic acid was dissolved in a mixture of 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid, heated on a steam bath for 3 hours and then concentrated in vacuo. The residue was dissolved in 5 ml of water and 1N sodium hydroxide was added to pH 7. The resulting solid was collected, washed with water and dried, giving 188 mg of the desired product, mp 202°-204° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:17]1[C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=[C:18]1[C:25]([OH:27])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22]([C:21]1[O:17][C:18]([C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:19][CH:20]=1)=[O:24])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1ccc(C(=O)O)o1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)o1
Yield: 78.1 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 640 mg (4.1 mmol) furan-2,5-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.7 g (78%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[Cl:1][C:2]1[C:7]([O:8][CH3:12])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COc1c([N+](=O)[O-])ccnc1Cl
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of 2-chloro-4-nitro-pyridin-3-ol (1.05 g, 6.02 mmol) in acetonitrile (45 mL) and methanol (5 mL), trimethylsilyldiazomethane (2M in hexane, 3.9 mL, 7.8 mmol) were added slowly. After 30 minutes, mixture was concentrated and residue was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1) to give 2-chloro-3-methoxy-4-nitro-pyridine as a white solid (0.77 g, 68%). 1HNMR (CDCl3, 400 MHz) δ 8.35-8.34 (d, J=5.1 Hz, 1H), 7.58-7.56 (d, J=5.2 Hz, 1H), 4.08 (s, 3H).