Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[C:15](=N)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO.ClCCCl>[C:15](=[N:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=[CH:5]2)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(Cl)nccc2cc1N
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc2c(Cl)nccc2cc1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a solution of 1-chloro-7-methyl-isoquinolin-6-ylamine (0.1 g, 0.52 mmol) in MeOH (5 mL) at 0° C. is bubbled HCl gas for 1 minute, then the solvent is removed in vacuo. The remaining white solid is diluted with 1,2 dichloroethane and benzophenone imine (0.15 mL, 0.89 mmol) is added. The resulting suspension is heated to reflux for 48 hours, then cooled to room temperature and concentrated to dryness. The crude material is diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography using 10% EtOAc/hexanes as the eluent to afford the title compound (0.159 g, 0.45 mmol) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].BrCC1C=CC=C(F)C=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: N#Cc1ccccc1CBr
Agent: Fc1cccc(CBr)c1
Product: N#Cc1ccccc1COc1cccc(N)c1

Procedure:
3-Nitro-phenol was reacted with 2-bromomethyl-benzonitrile according to the procedure from Example 199A substituting 2-bromomethyl-benzonitrile for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [C:1](=O)(OC)OC.[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[N:13]([CH3:1])[CH:12]=1)=[O:10]
Reactant: COC(=O)OC
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c2cc(Br)ccc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Alternate procedure: Add dimethyl carbonate (1.3 L, 12.4 mol) to a mixture of 6-bromo-1H-indole-3-carboxylic acid methyl ester (1.3 kg, 5.1 mol) and potassium carbonate (1.41 kg, 10.2 mol) in DMF (6.0 L) at room temperature. Heat the mixture to 130° C. and stir overnight. Cool the reaction mixture to ˜3° C. and add ice-cold water (6 L). Filter the resulting solid, wash with methanol (2 L) and dry in a vacuum oven to afford 1.1 kg (82%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C[C:15](=[O:19])[O:16]CC>>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[C:15]([OH:19])=[O:16]
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(C)=O
Product: O=C(O)C(O)c1ccc(F)cc1C(F)(F)F

Procedure:
The 2-trifluoromethyl-4-fluorobenzaldehyde (48.4 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 50.1 g. (84%). EA, MS(FD).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:54][CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[CH2:50][CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
236(b) A mixture of 1,1-dimethylethyl 4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)-amino]methyl}-5′-(methyloxy)-3-biphenylyl]methyl}hexahydro-1H-1,4-diazepine-1-carboxylate (130 mg, 0.19 mmol) in 25% TFA in DCM (3 mL) was stirred at RT for 2 h. It was purified by preparative hplc (NH2OH condition), eluting with 10 to 90% CH3CN in water. The product-containing fractions were dried under GeneVac to give a solid. It was purified using a Gilson HPLC (with 0.1% TFA condition) and eluting with 10 to 90% CH3CN in water. Product-containing fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-(hexahydro-1H-1,4-diazepin-1-ylmethyl)-5-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide as a white solid (45 mg, 31%). LC-MS m/z 759 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(SC)C=CC=CC=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:24]=[N:25][NH:26][S:27]([NH:30][C:31]([N:33]2[CH2:36][C@H:35]([NH:37]C(=O)OCC3C=CC=CC=3)[C:34]2=[O:48])=[O:32])(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[OH:23]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:37][C@H:35]1[CH2:36][N:33]([C:31]([NH:30][S:27]([NH:26][N:25]=[CH:24][C:19]2[CH:20]=[CH:21][C:22]([OH:23])=[C:17]([OH:16])[CH:18]=2)(=[O:28])=[O:29])=[O:32])[C:34]1=[O:48]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NN=Cc2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NN=Cc2ccc(O)c(O)c2)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 22 ml of trifluoroacetic acid and 5.8 ml of thioanisole was cooled to 0° C., and 5.5 g (11.5 mmol) of (S)-[1-[[[[2-[(3,4-dihydroxyphenyl)methylene]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester were added. After stirring overnight at room temperature, the excess trifluoroacetic acid was evaporated in vacuo and the residue triturated with ether. The trifluoroacetic acid salt was filtered off by suction and dried in vacuo; yield: 2.64 g.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]=2)[CH2:5][C@@H:4]([C:20](O)=[O:21])[NH:3]1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:46][C@H:47]([C:54]([N:56]1[CH2:63][CH2:62][CH2:61][C@H:57]1[C:58]([NH2:60])=[O:59])=[O:55])[CH2:48][C:49]1[N:53]=[CH:52][NH:51][CH:50]=1>C(N(CC)CC)C.CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:10]=2)[CH2:5][C@@H:4]([C:20]([NH:46][C@H:47]([C:54]([N:56]2[CH2:63][CH2:62][CH2:61][C@H:57]2[C:58]([NH2:60])=[O:59])=[O:55])[CH2:48][C:49]2[N:53]=[CH:52][NH:51][CH:50]=2)=[O:21])[NH:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N[C@H](C(=O)O)C2
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O)C2
Reaction time: 1.5 h
Yield: 33.3 %

Procedure:
A mixture of (3S)-1-oxo-7-tert.-butyloxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (680 mg), N-hydroxysuccinimide (280 mg), DCC (500 mg) and DMF (7 ml) is stirred for 1.5 hours. L-Histidyl-L-prolinamide.2HBr (990 mg) and triethylamine (1 ml) are added to the mixture. The mixture is stirred for 2 days. Insoluble materials are filtered off, and the filtrate is distilled under reduced pressure to remove DMF. The residue is dissolved in 20% citric acid, and washed with chloroform. The washed solution is adjusted to pH 9, and the solution is passed through a column (2.6×20 cm) packed with CHP-20P resin. The column is washed with water (one liter) and 30% methanol (1.5 liter) successively, and then the product is eluted with 50% methanol. The fraction positive to Pauly reagent are collected, and the collected solution is lyophilized, whereby Nα -[(3S)-1-oxo-7-tert.-butyloxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-L-histidyl-L-prolinamide (400 mg) is obtained. Yield: 33.3%.
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[CH:22]1OCC[O:23]1>C(O)(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[CH:22]=[O:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C3OCCO3)c2)c1=O
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reaction time: 5 h

Procedure:
5 ml of water were added to a solution of 1.9 g of 3-(4-chloro-3-(1,3-dioxolan-2-yl)-phenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 45 ml of glacial acetic acid. After stirring had been carried out for 12 hours at about 20-25° C. and for a further 5 hours at 40-50° C., 150 ml of water were stirred into the mixture. Thereafter, the precipitate formed was isolated, washed with water and petroleum ether and dried.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24]>>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Product: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11]
Reactant: CC(=O)c1ccc(OCC(C)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(C)(F)F)c(Cl)c1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (696 mg, colorless oil) from 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanone (610 mg, 2.45 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (446 mg, 3.68 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2.[CH2:22](I)[CH3:23]>>[O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]([CH2:22][CH3:23])[C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2
Reactant: CCOC(=O)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Reactant: CCI
Product: CCOC(=O)c1cn(CC)c2c(=O)oc3ccccc3c2c1=O
Yield: 75.4 %

Procedure:
Prepared from ethyl 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]-pyridine-2-carboxylate (9.5 g, 0.033 mole) and ethyl iodide (20.8 g, 0.134 mole) by the method described for Ex. 6. Recrystallization from dimethylformamide gives white crystals (7.8 g, 75%), m.p. 180-181.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].O.CO[CH2:19][CH2:20]OC>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:19]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9])=[CH2:20]
Reactant: COCCOC
Reactant: Oc1ccc(F)cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1cc(F)ccc1O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Nitrogen was bubbled through a mixture of 2-bromo-4-fluorophenol (1.6 g, 8.38 mmol), vinylboronic anhydride pyridine complex (95%, 806 mg, 3.35 mol) and potassium carbonate (1.17 g, 8.38 mmol) in 1,2-dimethoxyethane (15 mL) for 30 minutes. To this mixture was added palladium tetrakis(triphenylphosphine) (97.2 mg, 0.084 mmol). The reaction was allowed to stir at 90° C. for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with aqueous sodium hydroxide solution (1 N, 100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptanes) afforded the title compound as a white solid. Yield: 1.03 g, 7.46 mmol, 89%. 1H NMR (400 MHz, CDCl3) δ 4.91 (br s, 1H), 5.41 (dd, J=11.1, 1.0 Hz, 1H), 5.74 (dd, J=17.6, 1.0 Hz, 1H), 6.74 (dd, J=8.8, 4.7 Hz, 1H), 6.82-6.95 (m, 2H), 7.10 (dd, J=9.5, 3.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][CH:50]([OH:62])[CH2:51][N:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH2:61][N:52]1[CH2:51][CH:50]([OH:62])[CH2:49][NH:48][C:18]([C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][CH:21]=1)[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)O)c2)CC1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 28 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
The solution of 3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (100 mg, 0.31 mmol) and HATU (119 mg, 0.31 mmol) in DCM (10 mL) was stirred at 28° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (64.4 mg, 0.31 mmol) and DIPEA (48.4 mg, 0.38 mmol) was added and the resulting solution was stirred at 28° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the crude title product (150 mg, Yield 94%). LCMS (m/z): 509.2 (M+1).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH2:17][CH:16]3[CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=4[C:15]3=[N:14]2)=[CH:9][CH:8]=1.[H-].[Na+].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH2:17][CH:16]3[CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[CH:24][C:23]=4[C:15]3=[N:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)CCCCl
Reactant: O=C1CC2CSc3ccc(O)cc3C2=NN1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2c(c1)C1=NN(c3ccc(Cl)cc3)C(=O)CC1CS2
Temperature: 25 °C
Yield: 9.3 %

Procedure:
To 50 ml of dry dimethylformamide is added 4.5 g of 2-(4-chlorophenyl)-9-hydroxy-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one, and 0.7 g of 60% sodium hydride is added thereto while stirring at room temperature. After stirring at room temperature for 1 hour and addition of 2 g of 3-dimethylaminopropyl chloride, the mixture is stirred under heating at 40°-50° C. for 3 hours. After the completion of the reaction, the reaction mixture is poured into a large amount of water and the mixture is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent is distilled off. The residue is subjected to column chromatography and the eluate is converted into its fumarate to give 0.52 g of 2-(4-chlorophenyl)-9-(3-dimethylaminopropoxy)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.fumarate, as yellow crystals, m.p. 208°-210° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O>[Zn].C(O)(=O)C>[NH2:1][C:4]1[C:13]([C:14]([F:17])([F:15])[F:16])=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2ccncc2c1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc2ccncc2c1C(F)(F)F

Procedure:
Reducing the 7-nitro group of 7-nitro-8-trifluoromethylisoquinoline with zinc and acetic acid by the procedure of Example 17 gives 7-amino-8-trifluoromethylisoquinoline. Hydrogenating by the procedure of Example 9 gives 7-amino-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:27]([OH:29])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O>[C:27]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([OH:29])=[O:28]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with L-tyrosine in H2O to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: BrCCCCCBr
Product: COC(=O)C1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1
Yield: 90 %

Procedure:
Using the procedure and molar proportions of example 71, 1 g of racemic-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester was alkylated with 1,5-dibromopentane giving racemic-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless solid, mp 72.5°-74.5° C. in 90% yield after purification by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21].[Cl-].[NH4+].CC[N:32](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][CH2:12][C:13]([CH3:17])([CH3:18])[C:14]([NH2:32])=[O:15])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NCC(C)(C)C(=O)O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC[C@@H](NCC(C)(C)C(N)=O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Yield: 5.2 %

Procedure:
Step 5 To a solution of crude 3-{(R)-1-[4-Chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propylamino}-2,2-dimethyl-propionic acid (1.15 mmol) in DMF (7 mL) was added ammonium chloride (315 mg, 5.8 mmol, 5 eq), DIPEA (1.41 mL, 8.1 mmol, 7 eq.) and then HATU (661 mg, 1.74 mmol, 1.5 eq.) and the reaction stirred for 18 h. The mixture was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous was extracted with further EtOAc (20 mL) and then the combined organic phase washed with water (3×20 mL) and brine (20 mL) before it was dried (MgSO4), filtered and concentrated. Purified by prepHPLC, basic conditions, and then concentrated. Dissolved in DCM and 1.1 eq. 2 M HCl in Et2O was added. Concentrated and dried in a vacuum oven to give 3-{(R)-1-[4-Chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propylamino}-2,2-dimethyl-propionamide (26 mg, 0.06 mmol).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][CH:9]([F:42])[N:10]1[C:14]2[C:15]([O:33][C@@H:34]([C@H:36]3[CH2:40][NH:39][C:38](=[O:41])[CH2:37]3)[CH3:35])=[N:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[CH:18][C:13]=2[N:12]=[CH:11]1.CCN(C(C)C)C(C)C.[O:52]1[CH2:55][C:54](=O)[CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[F:42][CH:9]([F:8])[N:10]1[C:14]2[C:15]([O:33][C@@H:34]([C@H:36]3[CH2:40][NH:39][C:38](=[O:41])[CH2:37]3)[CH3:35])=[N:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:54]5[CH2:55][O:52][CH2:53]5)[CH2:27][CH2:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: O=C1COC1
Reactant: COc1cc(-c2cc3ncn(C(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(-c2cc3ncn(C(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C2COC2)CC1
Temperature: 52.5 °C
Reaction time: 18 h

Procedure:
The crude TFA salt of (R)-4-((R)-1-((3-(difluoromethyl)-6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: 3.67 (0.064 mmol) was dissolved in THF (1 mL) and iPr2NEt (12 μL, 0.07 mmol) was added followed by oxetan-3-one (18 μL, 0.30 mmol) and sodium triacetoxyborohydride (61 mg, 0.29 mmol). The reaction mixture was stirred at 50-55° C. for 18 h and was diluted with water, 5% (w/v) aqueous Na2CO3, and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-20% MeOH in DCM) to yield (R)-4-((R)-1-((3-(difluoromethyl)-6-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (3.70).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][C:6]1[CH:12]=[CH:11][C:9](N)=[CH:8][C:7]=1[S:13][CH3:14].[BrH:15]>S(=O)(=O)(O)O.C(O)(=O)C.O.[Cu]Br>[Br:15][C:9]1[CH:11]=[CH:12][C:6]([CH3:5])=[C:7]([S:13][CH3:14])[CH:8]=1
Reactant: Br
Reactant: CSc1cc(N)ccc1C
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CSc1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A cooled solution of sodium nitrite (5.8 g) in concentrated sulphuric acid (50 ml) was added dropwise to a stirred solution of 4-methyl-3-methylsulphenylaniline (12.8 g) in glacial acetic acid at 20° C. The resulting suspension was added to a mixture of copper (I) bromide (12 g), aqueous hydrobromic acid (48-50%) and ice. The mixture was stirred at room temperature for 3 hours then diluted with water and extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydroxide (2M), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with hot cyclohexane and filtered. The filtrate was evaporated to dryness to give 4-bromo-2-methylsulphenyltoluene (8.6 g) as a brown oil, NMR (CDCl3): 2.15(s,3H), 2.2(s,3H), 6.5-7.1 (m,3H).