Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:19]=[C:20]2[N:28]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[S:21]2)=[C:4]([F:30])[CH:3]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:19]2[C:22](=[O:29])[N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:20]2=[S:21])=[C:4]([F:30])[CH:3]=1
Reactant: O=c1sc(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)n2n1CCCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1n(-c2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)c(=S)n2n1CCCC2
Yield: 100 %

Procedure:
9-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-8-thia-1,6-diazabicyclo[4,3,0]nonan-7-one (see Example 8) (0.2 g) was mixed with methanol (18 ml) and a catalytic amount of sodium methoxide added. The mixture was heated at reflux for 0.5 hour and the solvent removed under reduced pressure. Column chromatography (silica gel, hexane:ethyl acetate, 3:2) yielded the product (0.2 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[BrH:13]>>[Br:13][C:6]1[CH:5]=[CH:4][N+:3]([O-:12])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: Br
Product: Cc1c(Br)cc[n+]([O-])c1C
Temperature: 100 °C

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine N-oxide (5 g, 29.7 mmol) and hydrogen bromide (30% wt in acetic acid, 100 mL) was heated for 48 hours at 100° C. The mixture was then filtered, washing through with 2M sodium hydroxide and the filtrate was extracted with dichloromethane (×3). The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 50:50, to afford the title product as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1.C(O)(C(F)(F)F)=O.C(#N)C.[OH-].[NH4+]>C(Cl)Cl>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: C=CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccc4cn(C)nc4c3)c12
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1c[nH]c2ncnc(-c3ccc4cn(C)nc4c3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prop-2-en-1-yl 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate was dissolved in DCM (1.0 mL) and then TFA (0.91 mL, 12 mmol) was added. The resulting solution was stirred for 2 hours at room temperature before being concentrated in vacuo. Acetonitrile (0.50 mL) and ammonium hydroxide (0.50 mL, 3.6 mmol) were added to the residue and the solution was heated to 50° C. for 3 hours. The reaction was concentrated in vacuo and purified by reverse phase chromatography using a 5-35% acetonitrile gradient in water with 0.1% TFA modifier. Pure fractions were free-based by extracting from a saturated sodium bicarbonate solution using 3:1 CHCl3:IPA (×3). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford prop-2-en-1-yl 4-(2-methyl-2H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid. LRMS (ESI) calcd for C18H16N5O2 [M+H]+: 334, found 334. 1H NMR (600 MHz, DMSO-D6) δ 13.04 (s, 1H), 8.96 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.81 (m, 1H), 7.79 (dd, 1H, J=8.4, 0.8 Hz), 7.39 (dd, 1H, J=8.4, 1.4 Hz), 5.5 (m, 1H), 4.97-5.04 (m, 2H), 4.30 (dm, 2H, J=5.7 Hz), 4.25 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O=[Pt]=O.C(O)C>[C:12]1([CH2:11][NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCCCCCCN
Agent: O=[Pt]=O
Solvent: CCO
Product: c1ccc(CNCCCCCCCCNCc2ccccc2)cc1

Procedure:
Combine 14.4 g (0.1 mol) of 1,8-octanediamine, 20.3 ml (0.2 mol) of benzaldehyde, 0.3 g PtO2 and 150 ml ethanol and treat the mixture with H2 at 45 lb/in2 in a shaker flask until no more gas is taken up. Remove the catalyst by filtration and remove the solvent at reduced pressure to yield the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH:3]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[N:15]=[CH:14][N:13]=1
Reactant: OC1CCCCCC1
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc(OC2CCCCCC2)ncn1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.25 g of cycloheptanol was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.3 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.43 g of 4-chloro-6-cycloheptyloxypyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([C:21]([CH3:29])([C:23]2[NH:24][CH:25]=[C:26]([CH3:28])[N:27]=2)[CH3:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH:39]=O)=[CH:32][CH:31]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:39][CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[CH:15][C:14]([C:21]([CH3:29])([C:23]2[NH:24][CH:25]=[C:26]([CH3:28])[N:27]=2)[CH3:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCN)c1
Reactant: O=CCCCc1ccncc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCNCCCCc2ccncc2)c1

Procedure:
Prepared essentially as described in EXAMPLE 3.2D starting from 2-{2-(3,5-dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H-imidazol-2-yl)ethyl]-1H-indol-3-yl}ethylamine (97 mg) and using 4-pyridin-4-yl butyraldehyde to give the title compound (73 mg). m/e=520 (M+1)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:23])([CH3:22])[CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Br:24]Br.CO.O>N1C=CC=CC=1>[Br:24][C:9]1[C:10]2[C:11](=[O:21])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:20])[C:19]=2[C:6]([NH:5][CH2:4][C:3]([CH3:23])([CH3:22])[CH2:2][OH:1])=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: CC(C)(CO)CNc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CC(C)(CO)CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 92.5 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 1-[(3-hydroxy-2,2-dimethylpropyl)amino]anthraquinone (88.0 g, 0.28 mol) in pyridine (400 mL) is added bromine (48.0 g, 0.30 mol) with vigorous agitation, allowing the temperature to rise to about 40° C. The reaction is completed by heating at 90 to 95° C. for 6 hours and then allowed to cool. Methanol (200 mL) is added, stirring continued for about 2 hours at room temperature and the product is then drowned into water with thorough stirring. The solids are collected by filtration, washed with water and dried in air to give 101.3 g of 4-bromo-l-[(3-hydroxy-2,2-dimethyl-propyl) amino]anthraquinone. The identity of the product is confirmed by mass spectrometry analysis.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH3:13][C:14]1[C:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=3)[CH2:23][CH2:24]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Yield: 87.9 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (3.84 g) described in Preparation Example 76 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (3.66 g) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (6.17 g) was obtained.
Reaction SMILES: NC1C=NC=CC=1[C@@H:8]1[O:13][C@H:12]([CH3:14])[C@:11]([OH:16])([CH3:15])[C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9]1.[CH3:25][N:26]1[C:30](C=O)=[C:29]([N+:33]([O-])=O)[CH:28]=[N:27]1>>[NH2:33][C:29]1[CH:28]=[N:27][N:26]([CH3:25])[C:30]=1[C@@H:8]1[O:13][C@H:12]([CH3:14])[C@:11]([OH:16])([CH3:15])[C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:9]1
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Reactant: C[C@H]1O[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Product: C[C@H]1O[C@@H](c2c(N)cnn2C)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O

Procedure:
Prepared in an analogous manner to tert-butyl ((2R*,3S*,4R*,6R*)-6-(3-aminopyridin-4-yl)-3-hydroxy-2,3-dimethyltetrahydro-2H-pyran-4-yl)carbamate (WO2012/004217), replacing 3-nitroisonicotinaldehyde with 1-methyl-4-nitro-1H-pyrazole-5-carbaldehyde (Intermediate 3).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.Cl>>[ClH:1].[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:2]3[C:3]4[CH:10]=[CH:9][NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2cc[nH]c2n1

Procedure:
Following the procedure described in Example 1, the title compound was prepared from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 5-aminoindole (7%). HRMS: Calcd. 250.1093, Found 250.1081; anal. RP18-HPLC RT: 2.58 min; HCl salt MP: 218-221° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=O)=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:43][C:44]1([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])[CH2:47][NH:46][CH2:45]1>CN(C=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([N:46]2[CH2:47][C:44]([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])([OH:43])[CH2:45]2)=[O:20])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C1(O)CN(C(=O)c2nn(C)c(=O)cc2Nc2ccc(I)cc2F)C1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a suspension of 4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.13 mmol) in DMF (2 mL), prepared using similar procedures to those described in Reference 4, at room temperature was added 1-hydroxybenzotriazole (36.3 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol) and the reaction was stirred for 2 hours. 1,1-Dimethylethyl [(1S)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (30 mg, 0.13 mmol), prepared using procedures similar to those in Example 28, and triethylamine (0.04 mL) were added and the mixture was stirred for 15 hours. The reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The organic layer was washed with 5% lithium chloride solution, saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product as yellow oil. The oil was purified by column chromatography (silica gel, ethyl acetate) to afford 1,1-dimethylethyl {(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate as a yellow oil (55 mg, 73% yield): 1H NMR (400 MHz, CDCl3): 10.24-10.23 (m, 1H), 7.52-7.50 (m, 2H), 7.12-7.07 (m, 1H), 6.10-6.09 (m, 1H), 5.13-5.09 (m, 1H), 4.91-4.82 (m, 1H), 4.60-4.39 (m, 2H), 4.10-4.08 (m, 1H), 4.00-3.87 (m, 2H), 3.70 (d, 3H), 1.43 (s, 9H), 1.24-1.20 (m, 3H); MS (EI) for C22H27FIN5O5: 588 (MH+).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])(=O)C.[K+]>C(#N)C>[C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Reactant: COc1ccc(B(O)O)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1
Temperature: 75 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 317 mg) in acetonitrile (5 mL) under nitrogen was treated with 4-methoxyphenylboronic acid (96 mg) followed by an aqueous solution of potassium acetate (2M, 0.65 mL) and 1,1 bis(bi-tert-butylphosphino)ferrocene palladium dichloride (8 mg). The reaction mixture was stirred at 75° C. for 18 h and then evaporated, dissolved in dichloromethane and absorbed onto silica. Purification by chromatography on silica eluting with 50% ethyl acetate in isohexane and then 100% ethyl acetate afforded the sub-titled compound as a solid (120 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2)[CH:2]=[CH2:3].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[H-].[Na+].O>CN(C)C=O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH2:17][N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=3)[C:11]2=[O:15])=[CH:21][CH:22]=1
Reactant: C=CCOc1ccc2c(c1)CCNC2=O
Reactant: Fc1ccc(CCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O

Procedure:
To a solution of 6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (10.6 g, 52 mmol) and 1-bromo-3-(4-fluorophenyl)-propane (17 g, 78 mmol) and KI (430 mg, 2.6 mmol) in dimethyl formamide (DMF) (125 mL) is added NaH (3.1 g, 78 mmol). After 4 hours the reaction mixture is poured into H2O (500 mL) and the resulting suspension is extracted with EtOAc (3×300 mL). The combined organic extracts are washed with H2O (5×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:1 EtOAc/hexane) to yield 2-[3-(4-fluorophenyl)-propyl]-6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][OH:5].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>ClCCl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][O:5][CH3:17]
Reactant: COS(=O)(=O)OC
Reactant: OCc1c(F)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
2-Chloro-6-fluorobenzyl alcohol (50 g) was stirred in dichloromethane and a solution of sodium hydroxide (32 g) in water was added. After 30 minutes stirring the mixture was cooled to 0° C. when dimethyl sulphate (47 g) and tetrabutyl-ammonium hydrogen-sulphate (1 g) were added dropwise. The mixture was allowed to warm to room temperature and stirred for 3 hours. It was quenched with water and extracted with dichloromethane. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue distilled under reduced pressure yielding 1-chloro-3-fluoro-2-methoxymethylbenzene (27.3 g) b.p. 82°-95° C./24 mm Hg.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[C@H:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[Cl:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([C:57](O)=[O:58])=[CH:51]2.C(N(C(C)C)CC)(C)C>O.CO.CN(C)C=O>[C:20]([CH2:19][C@H:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:24])[C@@H:9]1[NH:8][C:57]([C:52]1[NH:53][C:54]2[C:50]([CH:51]=1)=[CH:49][C:48]([Cl:47])=[CH:56][CH:55]=2)=[O:58])([O:22][CH3:23])=[O:21]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C[C@@H]1c2ccccc2NC(=O)[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C[C@H]1c2ccccc2NC(=O)[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A 1 mL reaction vessel was charged with trans 3-amino-4-carbomethoxymethyl-3,4-dihydrocarbostyril trifluoroacetic acid salt (13 mg, 0.04 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (9 mg, 0.05 mmol), 1-hydroxy-7-azabenzotriazole (7 mg, 0.05 mmol), 5-chloroindole-2-carboxylic acid (8 mg, 0.04 mmol) and N,N-dimethylformamide (0.3 mL). After the solids dissolved during stirring at room temperature under argon, diisopropylethylamine (14 mg, 0.11 mmol) was added, and the solution was stirred for 1 h before it was diluted with water (0.2 mL) and methanol (0.8 mL). Purification by reverse phase preparative HPLC using trifluoroacetic acid containing solvents gave the title compound (8.5 mg, 56% yield) as a white solid. 1H NMR (d8-THF, 400 MHz) δ 11.2 (s, 1H), 9.6 (s, 1H), 8.06 (d, 1H, J=8.9 Hz), 7.64 (d, 1H, J=1.9 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.24–6.87 (m, 6H), 4.84 (dd, 1H, J=8.8, 13.0 Hz), 3.67 (m, 1H), 3.59 (s, 3H), 2.89 (d, 2H, J=6.2 Hz). HPLC/MS [M+H]+, 412.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1>[Pd].C(O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:11]2[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=2[CH2:9][CH2:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:23])=[CH:19][CH:18]=1
Reactant: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(N)cc1

Procedure:
Reduction of 2'-[2-(1-methyl-2-piperidyl)ethyl]-4-nitrobenzanilide (6.5 g., 0.018 mole) in 100 ml. of ethanol employing 2 g. of palladium on carbon catalyst (10%) according to Example 2 (a) affords 4-amino-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide. Crystallization of the product from acetonitrile provides the analytically pure substance, m.p. 147°-148.5° C. (corr.).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:22][C:23](=[O:25])[NH2:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23](=[O:25])[NH:24][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOC(N)=O
Reactant: O=C(Cl)C1c2ccccc2Sc2ccccc21
Product: CCCCOC(=O)NC(=O)C1c2ccccc2Sc2ccccc21

Procedure:
The title compound, white solid, m.p. 151-154° C., MS: m/e 342.2 (M+H+) was prepared in accordance with the general method of example 6 from 9H-thioxanthene-9-carbonyl chloride and carbamic acid butyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=2)=[CH:13][CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)[CH3:41]>C1C=CC=CC=1>[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:15][CH2:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=2)[C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:10]=2)=[CH:48][CH:47]=1)[CH3:41]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OCC=C(c1ccc(-c2ccco2)cc1)c1ccc(-c2ccco2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(-c3ccco3)cc2)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 71.8 %

Procedure:
Reaction of 3,3-bis-(4-furan-2-yl-phenyl)-prop-2-en-1-ol (460 mg, 1.34 mmol), tributylphosphine (0.50 ml, 2.0 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (320 mg, 1.34 mmol) and azodicarboxylic dipiperidide (504 mg, 2.0 mmol) in benzene in an identical manner to example 3 gave the title compound (541 mg, 72%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[F:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccc(F)c(F)c4)c(C(=O)O)s3)c2cc1OC
Yield: 20.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-difluorophenylboronic acid (23.7 mg, 0.15 mmol) gave 4-(3,4-Difluoro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (8.7 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H); 8.22-8.32 (m, 1 H); 7.88-8.00 (m, 1 H); 7.80 (s, 1 H); 7.55 (dt, 1 H); 7.39 (s, 1 H); 3.88 (s, 3 H), 3.85 (s, 3 H). MS 418 m/z (M+1 ).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(N(C)C)=O>[O:30]=[C:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C(CBr)CCc1ccccc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(CCc1ccccc1)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.863 g, 1 eq.) was suspended in dimethylacetamide (DMA) (15 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (360 mg, 2.2 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 1-bromo-4-phenylbutan-2-one (1.1 g, 1.2 eq.) was added. The reaction was stirred at room temperature for 2 hours. The reaction was poured onto 100 mL water and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product, 5-(2-oxo-4-phenylbutyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.56 g) was used without purification. LCMS: 358 [M+H].