Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([CH2:10][C:11]([OH:13])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:25][N:26]1[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:40]>ClCCl>[O:40]=[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([C:36]([F:37])([F:39])[F:38])=[N:35][N:26]1[NH:25][C:11](=[O:13])[CH2:10][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)CC1(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CC1(c2ccccc2)CC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A solution of 2-(1-phenylcyclopropyl)acetic acid (0.063 g, 0.36 mmol) and oxalyl dichloride (0.042 mL, 0.48 mmol) in dichloromethane (1 mL) with a catalytic amount of DMF was stirred for 90 minutes, and concentrated. The material was re-dissolved in dichloromethane (1 mL) and the product from Example 11B (0.080 g, 0.35 mmol) was added, stirred for 2 hours, and concentrated. The residue was chromatographed on SiO2 (0-2% diethyl ether/dichloromethane) to give the title compound (52 mg) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.41-8.45 (m, 1H), 8.10-8.16 (m, 1H), 7.97-8.07 (m, 2H), 7.32-7.40 (m, 2H), 7.23-7.29 (m, 2H), 7.13-7.20 (m, 1H), 2.74 (s, 2H), 1.04-1.10 (m, 2H), 0.84-0.89 (m, 2H); MS (ESI−) M/Z 386 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]#[C:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34](Cl)=[O:35]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:12]=[C:5]1\[C:6](=[O:11])[NH:7][C:8]2[C:4]\1=[C:3]([C:20]#[C:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)=[CH:10][CH:9]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#Cc3cccnc3)c21
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(C#Cc3cccnc3)c21

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one (18 mg, 0.051 mmol) (from Example 69) was coupled with 2-thiopheneacetyl chloride (16.2 mg, 0.10 mmol) (Aldrich) in THF (2 mL) and saturated aqueous sodium bicarbonate (1 mL) at room temperature for 1 h, to yield (Z)-N-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-4-[(3-pyridinyl)ethynyl]-1H-indol-5-yl]-2-thiopheneacetamide. (Yield 7.7 mg, 32%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:16]12([C:26](Cl)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>C1COCC1.CCCCCC>[C:16]12([C:26]([O:10][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)([CH3:9])[CH3:8])=[O:27])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CC(C)(O)c1ccncc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 70.8 %

Procedure:
The method followed that described in Example 1, but using 2-(4-pyridyl)propan-2-ol (0.69 g, 5.0 mmol) in THF (20 ml), n-butyllithium (2.5 M; 2.0 ml, 5.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (1.09 g, 5.5 mmol) in THF (6 ml). Chromatography, on elution with ether-petrol-triethylamine 50:50:1, gave the title compound (1.06 g, 71%) as an oil. IR νmax 1730 cm-1 ; 1H-NMR (CDCl3) δ1.71 (6H, s, CMe2), 1.71 and 1.90 (12H, 2s, adamantyl CH2), 2.02 (3H, s, adamantyl CH), 7.23 (2H, d, J 6.1 Hz, Py 3 and 5-H), 8.56 (2H, d, J 6.1 Hz, Py 2 and 6-H). Anal. Calcd: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.17; H, 8.47; N, 4.64%.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH2:10][N:11]=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=1)[CH3:7].Br[CH2:19][CH:20]([CH:37]([CH3:39])[CH3:38])[CH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][CH:28]=[C:29]2[O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:24][CH:23]=1>O1CCCC1>[CH2:6]([O:8][C:9]1[CH:10]([CH2:19][CH:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:28]=[CH:27][CH:26]=3)[CH:31]=2)[CH:37]([CH3:38])[CH3:39])[N:11]=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=1)[CH3:7]
Reactant: COCCOc1cccc2ccc(CC(CBr)C(C)C)cc12
Reactant: CCOC1=NCC(OCC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC1=NC(CC(Cc2ccc3cccc(OCCOC)c3c2)C(C)C)C(OCC)=NC1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
3.03 ml of n-butyllithium (1.6M in hexane) are added dropwise at −40° C. to the suspension of 0.884 g of 3,6-diethoxy-2,5-dihydropyrazine in 12 ml of tetrahydrofuran. After 20 minutes, a solution of 1.265 g of 7-(2-bromomethyl-3-methylbutyl)-1-(2-methoxyethoxy)naphthalene in 5 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred further at −40″C. for 30 minutes, then warmed to −20° C. over 1 hour. After 18 hours, the reaction mixture is concentrated by evaporation—the residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (2×)—the combined organic phases are washed successively with water (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([Br:26])[C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[Br:26][C:20]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:18][CH:19]=1
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: COC(=O)c1c(Br)csc1N
Product: COC(=O)c1c(Br)csc1NC(=O)CN1C(=O)CCc2ccccc21

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (447 mg, 2.18 mmol) and methyl 2-amino-4-bromothiophene-3-carboxylate (516 mg, 2.18 mmol) according to protocol A. Retention time (min)=2.528, method [1], MS(ESI) 423.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(Br)c1O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Br)cccc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a solution of 3-bromo-2-hydroxy-benzaldehyde (2.72 g, 13.53 mmol) in DMF (70 mL) were added potassium carbonate (5.61 g, 40.59 mmol) and iodomethane (1.01 mL, 16.24 mmol). The reaction mixture was stirred at RT. After 18 h, the mixture was acidified with cooling using 1 M HCl (aq), extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as an oil (2.73 g, 94%). 1H NMR (300 MHz, CDCl3): δ 10.36 (s, 1H), 7.85-7.79 (m, 2H), 7.15 (dt, J=7.7 and 0.7 Hz, 1H), 4.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: COC(=O)c1ccc2c(Cl)n[nH]c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(Cl)n[nH]c2c1
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A solution of methyl 3-chloro-1H-indazole-6-carboxylate (891 mg, 4.2 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C., and then thereto was added dropwise diisobutylaluminum hydride (tetrahydrofuran solution, 1 mol/L, 12.7 mL, 12.6 mmol) at the same temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography hexane→hexane:ethyl acetate=2:1) to give (3-chloro-1H-indazol-6-yl)methanol (344 mg, 45%) as a yellow solid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[OH:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[OH:23][C:24]1[N:28]([CH2:2]/[CH:3]=[C:4]2/[C:5]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=3[O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/2=3)[C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1c(O)nc3ccccc31)c1ccccc1CO2

Procedure:
Compound h, 2.0 g and 4.3 g of 2-hydroxybenzimidazole were treated in a manner similar to Example 173 to give 0.3 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[CH3:22].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:15])=[CH:4][C:3]=1[CH3:22]
Reactant: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)c(C)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: COCCOc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)nicotinic acid (example CG) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 469.0893 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]2[C:13](=O)[CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1.O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]2[C:13]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1
Reactant: O=C1Cc2ccccc2Sc2cc(Cl)c(Cl)cc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CN1CCN(C2=Cc3ccccc3Sc3cc(Cl)c(Cl)cc32)CC1
Reaction time: 28 h

Procedure:
1-Methylpiperazine (15.0 g), followed by titanium tetrachloride (3.1 g) in benzene (45 ml), was added to a warm solution of 7,8-dichlorodibenzo(b,f)thiepine-10(11H)-one (8.85 g) (its preparation is described in Example 8) in benzene (75 ml). The mixture was refluxed while stirring for 28 hours, cooled and decomposed with water (100 ml). The resultant precipitate was filtered and washed with benzene and water. The benzene layer in the filtrate was separated, washed with water, dried over magnesium sulfate and taken down. The enamine base, obtained in nearly quantitative yield, was purified by crystallization from ethanol, m.p. 157°-159° C. Neutralization with maleic acid in ethanol yields the maleate, C23H22Cl2N2O4S, which is crystallized from ethanol; m.p. 229°-232° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([S:8](NC2C=CC=CC=2)(=[O:10])=[O:9])[CH:7]=1.NC1C=CC=CC=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([S:8]([NH:34][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:33][N:32]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Nc1ccccc1)c1cc(Br)ccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: Nc1ccccc1
Product: O=S(=O)(Nc1ccc(C(F)(F)F)cn1)c1cc(Br)ccc1Cl

Procedure:
The titled compound is prepared as described for 5-Bromo-2-chloro-N-phenyl-benzenesulfonamide (Intermediate F, step 2), by replacing aniline in this procedure with 5-trifluoromethyl-pyridin-2-ylamine
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:20]=1)[NH2:17].CS(O)(=O)=O>O1CCOCC1>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[C:19]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]3)[CH:20]=[C:14]([CH3:13])[CH:15]=2)[N:7]=1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COCCOc1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: COCCOc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
2-Chloro-4-(2-methoxyethoxy)pyrimidine (91 mg, 0.485 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (113 mg, 0.485 mmol) were dissolved in Dioxane (4 ml), and methanesulfonic acid (0.033 ml, 0.509 mmol) was added. The mixture was heated to 100° C. for 18 h. The mixture was allowed to cool to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to obtained 4-(2-methoxyethoxy)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (160 mg, 86%) as a brown solid. MS APCI: [M+H]+ m/z 386. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=5.8, 1H), 7.93 (s, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 6.26 (d, J=6.0, 1H), 4.58 (m, 2H), 3.77 (m, 2H), 3.42 (s 3H), 2.37 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:6]2[NH:5]1.I[CH3:29]>C1COCC1>[CH3:29][N:5]1[C@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2NC(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a suspension of NaH (8.5 mg of 60% in mineral oil, hexane-washed, 0.21 mmol) in 2 mL of THF at ambient temperature was added (3aR,9bS)-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 13, Part A (50 mg, 0.14 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodomethane (0.022 mL, 0.35 mmol) and the reaction was allowed to stir at ambient temperature for 18 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 3:1 hexane/EtOAc) to afford 40 mg (77%) of the title compound. LRMS (ESI): 371.12 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15][N:16]=[N+]=[N-])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15][NH2:16])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC[C@H]1CC[C@H](C(CCN=[N+]=[N-])NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCC[C@H]1CC[C@H](C(CCN)NC(=O)OC(C)(C)C)CC1
Reaction time: 18 h

Procedure:
A mixture of the azide from Step 15(0.72 g, 1.95 mmol) and 10% Pd/C (0.1 g) in MeOH (20 mL) was hydrogenated via a H2 balloon at rt for 18 h. Filtration and evaporation to dryness afforded the amine in a quantitative yield. LC/MS: 343.1 (MH)+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=O)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl-].[NH4+].C[N:20](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH2:20])[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.4 %

Procedure:
In a round-bottomed flask, (1R,3R)—N-Boc-1-aminocyclopentane-3-carboxylic acid (300 mg, 1.31 mmol) and ammonium chloride (210 mg, 3.93 mmol) were suspended in DMF (6 ml). HATU (547 mg, 1.44 mmol) and N,N-diisopropylethylamine (0.80 ml, 4.58 mmol) were added and the yellow suspension was stirred at room temperature for 72 h. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 97 mg (33%) of ((1R,3R)-3-carbamoyl-cyclopentyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:33])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[C:8]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)([CH3:3])[CH3:2].[CH2:34](Br)[CH3:35].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:34]([N:21]1[CH2:22][CH2:23][CH2:24][N:18]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[N:7]([CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:33])[C:16]3=[O:17])[CH2:19][CH2:20]1)[CH3:35]
Reactant: CCBr
Reactant: COc1cccc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCCN(c2ccc3nc(-c4cccc(OC)c4)n(CC(=O)NC(C)C)c(=O)c3c2)CC1
Yield: 10 %

Procedure:
A mixture of N-isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 2a) hydrochloride salt (50 mg, 0.103 mmol), ethyl bromide (22 mg, 0.21 mmol), and K2CO3 (43 mg, 0.31 mmol) in acetonitrile (5 mL) was heated to reflux for 24 h. The mixture was then cooled, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 2-[6-(4-ethylperhydro-1,4-diazepin-1-yl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 4a) (5.1 mg, 0.010 mmol, 10%) as the hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:20][C:15]1[C:14]([O:18][CH3:19])=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: [Br-]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reaction time: 18 h

Procedure:
A mixture of Example 151A (730 mg, 2.7 mmol) and tetrabutylammonium tribromide (1.3 g, 2.7 mmol) in DMF (15 mL) was treated dropwise with water (15 mL), stirred for 18 hours, and partitioned between water (250 mL) and ethyl acetate (250 mL). The organic phase was concentrated, diluted with dichloromethane (250 mL), washed with water (7×250 mL) and brine, dried (Na2SO4), filtered, concentrated and purified on silica gel with dichloromethane to provide the desired product. MS (ESI(+)) m/e 363, 365 (M+NH4)+, 368, 370 (M+Na)+; (ESI(−)) m/e 344, 346 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.50 (br s, 1H), 8.92 (s, 1H), 7.65 (d, 1H), 7.36 (d, 1H), 3.79 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10]Br)=[O:4].CO.[NH3:14]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][NH2:14])=[O:4]
Reactant: COC(=O)c1sccc1CBr
Reactant: N
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
3-Bromomethyl-thiophene-2-carboxylic acid methyl ester (1.297 g, 5.54 mmol) is dissolved in DMF (30 mL) and MeOH/NH3 is added (30 mL). The reaction mixture is stirred at room temperature for 1 hour, and concentrated in vacuo. Purification of the residue by silica gel column chromatography eluting with 95:5 and 93:7 DCM:MeOH affords the title compound (0.82 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][NH2:36])[CH:31]=[CH:32][CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:36][CH2:35][CH2:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1cccc(Cl)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Cl)c4)cc3)c(Cl)cc21
Reaction time: 48 h
Yield: 91.5 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (48.8 mg, 0.130 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 2-(3-chlorophenyl)ethylamine (22.2 mg, 0.143 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.8 mg, 0.155 mmol), and 1-hydroxy-7-azabenzotriazole (5.29 mg, 0.0389 mmol) at ambient temperature. After 48 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (61.1 mg, 0.119 mmol, 91.7% yield) as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH:24]1[CH:28]([CH3:29])[CH2:27][NH:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH:28]([CH3:29])[CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CNCC1CNCC1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-methylaminomethyl-4-methylpyrrolidine (0.34 g) and DBU (0.27 g) was refluxed for an hour and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.41 g) as white powder, mp 252°-254° C.