Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C#N.[H-].[H-].[H-].[H-].[Li+].[Al+3].C[OH:28].C(Cl)Cl.[OH-].[Na+]>C1COCC1.O>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[OH:28]
Reactant: CO
Reactant: CN(C)CCC(C#N)c1ccc(-c2ccncc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCC(O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-dimethylamino-2-(4-pyridin-4-yl-phenyl)-butyronitrile (680 mg, 2.56 mmol) in THF (5 mL) was added LiAlH4 (1M in THF, 26 mL, 26 mmol) and the mixture was stirred at room temperature for 16 h. TLC (10% MeOH/CH2Cl2) showed no starting material left and a new low Rf spot was formed. The mixture was treated with 1.74 mL of H2O, followed by 3.48 mL of 1N aqueous NaOH, and then 5.2 mL of H2O. After 30 min of stirring, the mixture was filtered and the filtrate was dried over Na2SO4 and concentrated to give 3-dimethylamino-1-(4-pyridin-4-yl-phenyl)-propan-1-ol as a yellowish solid, 300 mg (46%). 1H NMR (300 MHz, CDCl3): δ 8.75 (dd, 2H), 7.74 (m, 2H), 7.62 (m, 4H), 5.12 (dd, 1H), 2.82 (m, 1H), 2.64 (m, 1H), 2.44 (s, 6H), 1.97 (m, 2H).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)#[N:35]>>[CH3:24][O:23][C:22]1[C:2]([C:39]2[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[CH:37][CH:38]=2)=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]=2[CH:21]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccc(C#N)cc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 14 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 4-cyanophenyl boronic acid. The title compound (25 mg) was obtained as a beige solid, (yield=14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1I.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[C:39]1[CH:40]=[CH:41][C:36]([F:35])=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:38]=1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(I)c(Cl)c2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(-c3ccc(F)c(C(F)(F)F)c3)c(Cl)c2)cn1

Procedure:
Ethyl 3-(5-(2-(((3-chloro-4-iodophenyl)amino)methyl)-4,5-difluorophenyl)picolinamido)propanoate (123 mg, 0.21 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (85 mg, 0.41 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol), and K2CO3 (85 mg, 0.62 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.3 mL) and the resulting mixture was heated to 70° C. After 1 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([N:30]3[CH2:31][CH2:32][CH:27]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)=[CH:13][C:12]=2[N:4]2[CH2:9][CH2:8][CH:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCC(Cc4ccccc4)CC3)cc2N2CCC(Cc3ccccc3)CC2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 2.67 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine and 8.8 ml of 4-benzylpiperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 2 to give 4.1 g of the title compound as oil
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[CH3:24][NH:25][CH3:26].C1COCC1>CN(C=O)C.[Cl-].[Na+].O.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:25]([CH3:26])[CH3:24])=[O:12])[N:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([C:20]#[N:21])([CH3:23])[CH3:22])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: CC(C)(C#N)c1ccc(-n2c(CO)cc3cnc(Cl)nc32)cc1
Agent: [Mn+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1ccc(C(C)(C)C#N)cc1
Reaction time: 3 h

Procedure:
2-(4-(2-chloro-6-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropanenitrile (589 mg, 1.8 mmol), manganese dioxide (7.8 gm, 90 mmol) and 2 M dimethylamine solution in THF (4.51 ml, 9 mmol) were combined in 6 mL dry DMF. Reaction was stirred for 3 hrs whereupon the reaction appeared complete by LC/MS. Reaction was poured into brine and extracted into EtOAc. Combined organics were washed with water followed by brine and then dried over sodium sulfate. Volatiles were removed and the residue purified by NPLC (10-100% ethyl acetate in heptane, Analogix) to yield the pure desired compound. (345 mg, 52%). MS 367.7 m/z
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 75.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) propan-2-ol (90 mg, 0.135 mmol) was hydrolyzed with lithium hydroxide (14 mg, 0.270 mmol) in THF/methanol/water (5/2/1 mL) to yield 52 mg (63.0% yield) of desired product. 1H NMR (CD3OD, 400 MHz): δ 8.56-8.55 (d, 1H), 8.485-8.481 (d, 1H), 8.44-8.43 (d, 1H), 8.24 (s, 1H), 8.09-8.06 (dd, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.40-7.38 (q, 1H), 7.13-7.11 (m, 2H), 7.10-7.00 (m, 2H), 5.45 (s, 2H), 4.70-4.40 (bs, 2H), 4.30-4.20 (m, 1H), 3.90-3.50 (bs, 4H), 3.17-3.11 (m, 2H), 1.30-1.27 (m, 3H). MS: m/z=512.3 (M+1), HPLC: 98.72% in method A.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:11]([C:10]3[CH:9]=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 46.2 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (363 mg) described in Preparation Example 25 and 1-(3,5-dimethylpyridin-2-yl)piperazine (256 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (257 mg) was obtained.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].C1COCC1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Mg]Br.CO>ClC1C=CC=CC=1.C(Cl)Cl>[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: COc1ccccc1[Mg]Br
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: Clc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3OC)sc2c1
Yield: 61.8 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.0 g, 2.29 mmol) in chlorobenzene (10 mL) was treated with a 0.65 M THF solution of 2-methoxyphenylmagnesium bromide (11.0 mL, 7.11 mmol) (prepared from 2-bromoanisole, catalytic iodide, and magnesium turnings in THF) to provide after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 710 mg (62%) of the title compound as a yellow foam: 1H NMR d 1.44 (m, 2H), 1.60 (m, 4H), 2.48 (m, 4H), 2.72 (t, J=5.9 Hz, 2H), 3.51 (s, 3H), 3.87 (s, 3H), 4.06 (t, J=5.9 Hz, 2H), 6.65 (d, J=8.2 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 6.89 (t, J=7.4 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.33 (s, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H); 13C NMR d 23.6, 25.4, 54.0, 54.6, 55.1, 57.2, 65.6, 103.6, 104.9, 110.2, 113.2, 114.2, 120.1, 122.2, 124.1, 129.6, 130.1, 130.9, 131.5, 133.0, 139.3, 140.0, 155.3, 157.0, 161.9, 191.1; MS (FD) m/e 501 (M+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:35]1[CH2:44][CH2:43][CH2:42][C:41]2[C:40]([C:45]#[N:46])=[CH:39][CH:38]=[CH:37][C:36]1=2.BrC1C=CC=C2C=1CCCC2=O>C1COCC1.O>[CH3:12][O:13][CH:14]=[C:35]1[CH2:44][CH2:43][CH2:42][C:41]2[C:40]([C:45]#[N:46])=[CH:39][CH:38]=[CH:37][C:36]1=2
Reactant: N#Cc1cccc2c1CCCC2=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCCc2c(Br)cccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC=C1CCCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium bis(trimethylsilyl)amide (2 mL, 4 mmol, 2M in THF) was added to a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (1.47 g, 4.3 mmol) in dry THF (20 mL) at 0° C. for 35 min and a solution of 5-Oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile [prepared from 5-bromo-tetralone following the procedure described in PCT publication WO2004/071389A2, Intermediate 41](490 mg, 2.86 mmol) in THF (10 mL) added over 10 min. The mixture was stirred at 0° C. for 2 h and at room temperature for 1 h. Water was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried and concentrated. The crude product was purified via preparative-TLC (PE:EtOAc=10:1) to afford the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:35](=O)([O-])[O-].[K+].[K+].IC.Cl>C(#N)C>[OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH3:35])[C:21](=[O:25])[CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv), and Iodomethane (40 μL, 10 equiv) were mixed with acetonitrile (2.5 mL) and heated at reflux for 4 h. After being cooled to rt, the mixture was acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (14.4 mg. 52%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].Cl>CN(C)C1C=CC=CC=1>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[NH:1][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: CCCCC(=O)Nc1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of ethyl 4-amino-3-nitrobenzoate (49.5 g) and N,N-dimethylaniline (90 ml) was heated at 110° C. under nitrogen atmosphere. To the solution was added valeryl chloride (29 ml) and the mixture was stirred at 110° C. for 1.5 hours. After being cooled to room temperature, 1N hydrochloric acid was added until pH 2~3 to the reaction mixture. The aqueous solution was extracted with ethyl acetate. The organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified with silica gel column chromatography (ethyl acetate: n-hexane =1:5) to give ethyl 3-nitro-4-valerylaminobenzoate (67.5 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][C:27](=[O:29])[NH:26][C:25]=1[C:30](O)=[O:31]>>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[O:12])[CH2:9][CH2:10]1)[C:30]([C:25]1[NH:26][C:27](=[O:29])[O:28][C:24]=1[CH3:23])=[O:31]
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: Cc1oc(=O)[nH]c1C(=O)O
Product: Cc1oc(=O)[nH]c1C(=O)N(C)CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
The title compound was prepared from 3,5-dichlorobenzyl 4-(2-methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) and 5-methyl-2-oxo-2,3-dihydrooxazole-4-carboxylic acid analogously to Example 6;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([C:18](Cl)=[O:19])=[C:16]([CH:21]([CH3:23])[CH3:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.[BH4-].[Li+].O.C(OCC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([CH2:18][OH:19])=[C:16]([CH:21]([CH3:22])[CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Cl)n(-c2ccc(F)cc2)c(=O)c2ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1c(CO)n(-c2ccc(F)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A stirred solution of crude 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carbonyl chloride (21 g) in dry tetrahydrofuran (300 ml) was treated dropwise with a solution of lithium borohydride in tetrahydrofuran (26 ml; 2.0M) and the mixture stirred at room temperature for 18 hours. The reaction mixture was then treated dropwise with water (50 ml), diethyl ether (500 ml) and more water (200 ml) and the organic layer was separated, washed with water (200 ml) and brine (200 ml), dried over magnesium sulphate and evaporated to leave a yellow oil. This was triturated with a hot mixture of diethyl ether (200 ml) and n-hexane (400 ml) to give 2-(4-fluorophenyl)-3-hydroxymethyl-4-isopropyl-1-oxo-1,2-dihydroisoquinoline (13.7 g) in the form of a white solid, m.p. 157°-158° C. [Elemental analysis: C, 73.1; H, 5.7; N, 4.4%; calculated: C, 73.3; H, 5.8; N, 4.5%; NMR (in CDCl3): 1.55 (7H, d, J=8 Hz,), 3.65 (1H, sept, J=8 Hz), 4.4 (2H, s), 7.1-7.4 (4H, m), 7.5 (1H, t, J=8 Hz,), 7.7 (1H, t, J=8 Hz), 8.04 (1H, d, J=8 Hz), 8.5 (1H, d, J=8 Hz)].
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[NH:4].[Cl:15][C:16]1[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[CH:22][C:17]=1[C:18](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:15][C:16]1[CH:25]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[CH:23]=[CH:22][C:17]=1[C:18]1[O:1][N:2]=[C:3]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]=2[CH:7]=[CH:8][N:9]=[CH:10]3)[N:4]=1
Reactant: COC(=O)c1ccc(OC(C)C)cc1Cl
Reactant: N=C(NO)c1cccc2cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)c(Cl)c1
Yield: 13.7 %

Procedure:
N-hydroxy-5-isoquinolinecarboximidamide (D1, 30 mg, 0.160 mmol) was stirred in DMF (0.7 ml) with methyl 2-chloro-4-[(1-methylethyl)oxy]benzoate (D32; 40.3 mg, 0.176 mmol) and sodium hydride (60%; 4.61 mg, 0.115 mmol) in a Biotage Initiator microwave at 100° C. for 30 mins. The cooled mixture was concentrated under vacuum and the residue was purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)) to give the title compound as a pale yellow solid (8 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([Br:23])[CH:22]=1)[CH:18]=[O:19].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S1C=CC=C1[Mg]Br>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:19])[CH:20]=[C:21]([Br:23])[CH:22]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Agent: Br[Mg]c1cccs1
Product: OC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1

Procedure:
The title compound was prepared as described in Example 10 Step 2 with 3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-bromobenzaldehyde and phenylmagnesium bromide replacing 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde and 2-thienylmagnesium bromide, respectively.
Reaction SMILES: C([N:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2C=CC=CC=2C=O)[CH2:25][CH2:24]1.CN(C)C=O>C(OCC)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:4][C:5](=[O:13])[CH:6]=[CH:7][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:22]=2[N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: CC(=O)N(Cc1ccc(Cl)cc1)C(=O)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccccc2C=CC(=O)NCc2ccc(Cl)cc2)CC1

Procedure:
In a flame-dried 25 mL 3-neck round bottom flask equipped with a magnetic stir bar, 83 mg (2.07 mmol of a 60% oil dispersion) of sodium hydride was washed with hexane and covered with 1.0 mL of anhydrous N,N-dimethylformamide (DMF). To this was added 156 mg (0.517 mmol) of N-acetyl-N-(4-chlorobenzyl)phenylacetamide (prepared as above) and 84 mg (0.414 mmol) of 2-(4-methylpiperazin-1-yl)benzaldehyde with an additional 1 mL of DMF. The brown reaction mixture was stirred at 250C for 48 hours, diluted with ethyl acetate, washed with 1N lithium chloride (LiCl) followed by saturated aqueous sodium chloride. The organic layer was dried over calcium sulfate (CaSO4) and concentrated to an oil which was crystallized from about 1 mL of boiling ethyl acetate to give the title product as colorless crystals, 20 mg, m.p. 193-194° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][C:24]=4[F:35])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[F:35][C:24]1[CH:25]=[C:26]([C:29]2[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=2)[CH:27]=[CH:28][C:23]=1[C:20]1([C:17]2[N:13]3[CH2:14][CH2:15][S:16][C@:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]3=[N:19][N:18]=2)[CH2:21][CH2:22]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO)C5)CC3)c(F)c2)cn1
Yield: 89.9 %

Procedure:
A solution of the compound (3.87 g, 7.32 mmol) obtained in Example 81-2) and 4 M hydrochloric acid (1,4-dioxane solution, 15 mL) in methanol (30 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (20 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=30:70) to obtain the title compound (2.72 g, 90%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][C@H:21]([CH2:24][CH3:25])[CH2:22][OH:23].CN1CCCC1=O.C(N(CC)C(C)C)(C)C>O>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][C@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: CC[C@@H](N)CO
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12

Procedure:
To a mixture of the product of example 1 step c) (2.5 g) and (R)-(−)-2-amino-1-butanol (5 g) in a solvent of N-methylpyrrolidinone (10 ml) was added N,N-diisopropylethylamine (5 ml) and the resultant mixture heated at 100° C. for 10 hours. The mixture was poured into water and the product collected by filtration to give the subtitle compound (2.5 g)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](=[O:15])([O-])[O-:13].[K+].[K+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:2]2[C:3](=[CH:4][CH:5]=[CH:7][CH:8]=2)[C:12]([OH:13])=[O:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Product: Cc1ccc(Nc2ccccc2C(=O)O)c([N+](=O)[O-])c1
Temperature: 200 °C

Procedure:
2-1odobenzoic acid (5 g, 20.16 mmol), 4-methyl-2-nitroaniline (6.12 g, 40.32 mmol), potassium carbonate (2.8 g, 20.3 mmol) and Cul (0.2 g) were thoroughly mixed and heated to 200° C. for 1 hour. After cooling the solid reaction mixture was partitioned between ethyl acetate and aqueous sodium hydroxide (1M). The product precipitated from the aqueous phase on acidification with hydrochloric acid (4M). Yield 3.69 g, mp 209°-213° C.