Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:14]1([CH:17]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15]1>C(#N)C>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH:17]([CH:14]2[CH2:15][CH2:16]2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:32][CH:31]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(OC(c2ccc(Cl)cc2)C2CC2)cc1
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(OC(c2ccc(Cl)cc2)C2CC2)cc1

Procedure:
1,57 g of 2,6-difluorobenzoylisocyanate was added to a solution of 3,35 g 4-(α-cyclopropyl-4-chlorobenzyloxy)aniline in 30 ml of dry acetonitrile while stirring. After stirring for 1 hour at room temperature the formed precipitate was sucked off, washed with acetonitrile, and dried. The desired product was obtained in a yield of 2.90 g; melting point 185°-188° C. The structure was confirmed by means of CMR.
Reaction SMILES: CCN(S(F)(F)F)CC.[F:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32]O)[CH:30]=4)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[Cl-:36].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][Cl:36])[CH:30]=4)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: [Cl-]
Reactant: OCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Yield: 30 %

Procedure:
Diethylaminosulfatrifluoride (DAST, 160 mg) was added dropwise at −78° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline (300 mg) inmethylene chloride (10 ml) and the resultant mixture was stirred for 1 hr. Then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and the obtained residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) followed by conversion into a hydrochloride in a conventional manner to give the hydrochloride (100 mg) of the title compound as a white powder (yield: 30%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([OH:19])[CH3:18].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:17]([O:19][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH3:18]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanol and DBU in THF. ES-MS m/e (%): 332 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:22]=[CH:21][C:20](OC)=[CH:19][C:16]=1[CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14]2[C:15](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][N+:26]=1[O-:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: COc1ccc(C#CCCCCOCc2ccccc2)c(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: [O-][n+]1ccc2ccccc2c1CCCCOCc1ccccc1
Yield: 80.7 %

Procedure:
2-[2-(4-Benzyloxybutyl)ethynyl-5-methoxybenzaldehyde (2.60 g), hydroxylamine hydrochloride (0.63 g) and sodium acetate (0.78 g) were reacted in ethanol, (30 ml) at 60° C. for 2 hr. Potassium carbonate (2.0 g) and water (5 ml) were added to the resulting reaction mixture, which was then heated under reflux for 12 hr. The reaction solution was evaporated, and the resulting residue was extracted with methylene chloride, washed with brine, and then dried. The solvent was removed and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 2.0 g of the title compound as a brown amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]2C(=O)NC(=O)[C:14]2([O:23]CCC)C=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C[NH2:33]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:23][NH2:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCCOC12C=CC=C(NC(=O)OCc3ccccc3)C1C(=O)NC2=O
Solvent: CCO
Solvent: C1CCOC1
Product: NOCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of N-[3-(benzyloxycarbonylamino)-1-propoxylphthalimide (1.42 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). The solution was stirred at room temperature for 1 h. The solvent was evaporated and the residue passed through silica gel (3:1 ethyl acetate:hexane to ethyl acetate) to give the title compound as a white solid (870 mg, 97%). 1H-NMR (300 MHz, CDCl3) δ7.36 (m, 5H), 5.38 (br s, 2H), 5.09 (s, 2H), 5.08 (br s, 1H), 3.73 (t, J=5.9 Hz, 2H), 3.29 (q, J=6.2 Hz, 2H), 1.79 (pentet, J=6.2 Hz, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:17][C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-])=O)=[CH:14][CH:15]=3)[C:10]2=[O:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(O)(=O)C.Cl.O.[Cl-].[Ti+3].[Cl-].[Cl-]>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([CH2:17][C:16]3[C:11](=[CH:12][C:13]([NH2:18])=[CH:14][CH:15]=3)[C:10]2=[O:21])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(CC1)Cc1ccc([N+](=O)[O-])cc1C2=O
Agent: [Ti+3]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCC2(CC1)Cc1ccc(N)cc1C2=O
Reaction time: 2 h
Yield: 112.3 %

Procedure:
To a solution of 0.29 g (1.0 mmole) 1'-acetyl-1,3-dihydro-6-nitro-1-oxospiro[2H-indene-2,4'-piperidine] in 4 ml acetic acid was added 3.75 ml (4.3 mmoles) of 15% titanium (III) chloride solution in 20-30% aqueous hydrochloric acid dropwise and portionwise over 2 hours. The reaction mixture was made basic (pH 10) with saturated sodium bicarbonate solution and 10N sodium hydroxide solution, diluted with 50 ml water, and extracted with 3×50 ml ethyl acetate. The combined extracts were washed with 20 ml water and brine, dried, and the solvent was removed in vacuo to give 0.29 g crude 1'-acetyl-6-amino-1,3-dihydro-1-oxospiro[2H-indene-2,4'-piperidine].
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:12]([CH3:14])[CH3:13])=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.Cl>O1CCOCC1.Cl>[CH3:1][C:2]1[S:3][C:4]([CH:12]([CH3:14])[CH3:13])=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(C)sc1C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(C(=O)O)c(C(C)C)s1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Ethyl 2-methyl-5-(1-methylethyl)-1,3-thiazole-4-carboxylate (200 mg) was dissolved in 1,4-dioxane (2 ml). Hydrochloric acid (2 ml) was added and the mixture was heated at reflux under nitrogen for 18 h. One drop of concentrated hydrochloric acid was added and the mixture was heated at reflux for 72 h. The mixture was cooled to RT, the solvent was removed in vacuo and toluene (15 ml) was added. The solvent was removed in vacuo to give a brown oil which solidified on standing. The product was dried in a vacuum oven overnight to give the title compound (171 mg) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:19]([OH:22])(=O)=[O:20])[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:31])=O>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:19]([Cl:31])(=[O:22])=[O:20])[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(-c2cc(S(=O)(=O)O)c3ccncc3c2)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(S(=O)(=O)Cl)c3ccncc3c2)cc1
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 115.2 %

Procedure:
To a slurry of 7-(4-methoxy-phenyl)-isoquinoline-5-sulfonic acid (12.13 g, 38.5 mmol) in 1,2-dichloroethane (200 mL) and DMF (2.99 mL, 38.5 mmol) add oxalyl chloride (26.8 mL, 308 mmol) dropwise. Mechanically stir the slurry under nitrogen atmosphere while heating at 60-65° C. for 4 hr. Cool the slurry to −10° C. Wait for 30 min then filter. Wash the yellow solid with 20% ether/dichloromethane and dry under a nitrogen atmosphere affording the title compound (14.8 g) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:36])[CH3:35].O>ClCCl>[C:34]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:12]2[C:6]3[CH:7]=[N:8][C:9]4[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=4[C:5]=3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=3)[C:13]2=[O:26])(=[O:45])=[O:44])=[CH:41][CH:42]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added 4-acetylbenzene-1-sulfonyl chloride (35.35 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 12 mg (17%); 1H NMR (DMSO-d6, 300 MHz): δ 9.44 (s, 1H), 8.316-8.344 (d, 2H, J=8.4 Hz), 8.18-8.208 (d, 2H, J=8.4 Hz), 7.985-8.015 (d, 1H, J=9 Hz), 7.810-7.838 (d, 2H, J=8.4 Hz), 7.751-7.782 (d, 1H, J=9.3), 7.695-7.722 (d, 2H, J=8.4 Hz), 6.74 (s, 1H), 2.63 (s, 3H), 1.77 (s, 6H); MS: m/z 589 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([Cl:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CSC.B(F)(F)F.CCOCC.O>C(Cl)Cl>[Cl:28][CH:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:30][CH:29]=2)=[CH:17][CH:18]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: FB(F)F
Solvent: O
Solvent: CSC
Solvent: CCOCC
Product: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
Methyl 3-(4-{2-[4-(benzyloxy)phenoxy]ethyl}phenyl)-2-chloropropanoate (1.0 g, 2.4 mmol) and dimethyl sulfide (0.9 g, 14 mmol) was dissolved in 60 ml CH2Cl2. Boron trifluoride etherate (2.0 g, 14 mmol) was added droppwise to the stirred solution. The reaction mixture was stirred for two days at room temperature. Another equivalent (0.4 g, 2.87 mmol) boron trifluoride etherate was added and the stirring was continued overnight. Water was added. The phases were separated and the aqueous phase was extracted twice with CH2Cl2. The organic phases were pooled, washed (water, brine), dried (Na2SO4) and evaporated under reduced pressure. Further purification by preparative HPLC using a gradient of CH3CN/5% CH3CN-waterphase containing 0.1M NH4OAc gave 0.55 g of the desired product (yield 52%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([O:10][C:11]([N:13]1[CH:18]([C@@H:19]([OH:33])[C@@H:20]([NH:29][C:30](=[O:32])[CH3:31])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:14]1[CH3:40])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:33])[C@@H:20]([NH:29][C:30](=[O:32])[CH3:31])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:2][CH2:3][CH2:4][CH3:5])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:14]1[CH3:40])=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)C1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cccc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 102.5 %

Procedure:
Add 1-bromobutane (6 μL, 55.6 μmol) to a solution of 5-[2-(S)-acetylamino-1-(S)-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (25 mg, 50.5 μmol) and cesium carbonate (33 mg, 1.01 mmol) in N,N-dimethylformamide (250 μL). Heat to 60° C. for 3 hours. Dilute with ethyl acetate, wash with water, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 85:15 ethyl acetate:dichloromethane) to give the title compound (28.5 mg, 80%).
Reaction SMILES: [C:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[OH:29])[C:22]([NH:24][NH2:25])=[O:23]>>[C:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[N:25][NH:24][C:22](=[O:23])[C:21]2[CH:26]=[CH:27][C:28]([OH:29])=[C:19]([Cl:18])[CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: C=CC(=O)Oc1ccc(C=O)c2ccccc12
Product: C=CC(=O)Oc1ccc(C=NNC(=O)c2ccc(O)c(Cl)c2)c2ccccc12

Procedure:
The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1-naphthyl acrylate (from step C) and 3-chloro-4-hydroxy benzoic acid hydrazide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[N+:15]([CH3:18])([O-:17])=[O:16].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C>[N+:15]([CH2:18][CH2:10][C:9]1[CH:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(-c2ccccn2)c1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccc(-c2ccccn2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a mixture of 3-pyridin-2-yl-benzaldehyde (290 mg, 1.6 mmol) described in Manufacturing Example 84-1-1 and acetic acid (5 mL) were added nitromethane (0.65 mL, 12 mmol) and ammonium acetate (370 mg, 4.8 mmol), which was stirred for 2 hours at 100° C. The reaction mixture was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. A mixture of dimethyl sulfoxide (6 mL) and acetic acid (0.4 mL) was added to the resulting residue, and sodium borohydride (97 mg, 2.6 mmol) was added at room temperature while cooling appropriately. The reaction mixture was stirred for 10 minutes at the same temperature. Water was added to the reaction mixture at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The resulting residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (260 mg, 71%).
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>C(Cl)Cl.CO>[N:48]1([CH2:47][CH2:46][O:43][C:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]3[S:35][C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[CH:32][N:33]=3)=[CH:38][CH:39]=2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: ClCCN1CCCCC1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: c1cc(-c2cnc(Nc3ccc(OCCN4CCCCC4)cc3)s2)cs1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 1-(2-chloroethyl)-piperidine hydrochloride. Title compound: ES-MS: 386.0 [M+H]+; single peak at tR=6.26 min (System 1); Rf=0.36 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:27][C:26]([CH2:28][CH2:29][NH2:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:27][C:26]([CH2:28][CH2:29][NH:30][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[N:3]=3)=[O:13])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: Cn1nc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)c2ccccc21

Procedure:
The title compound was prepared as in Example 12 starting from N-methyl-indazole-3-carboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crude product was purified by flash chromatography using heptane/EtOAc as a gradient eluent (9:1-8:2). 1H NMR (400 MHz, DMSO-d6): 3.00 (2H, t), 3.64 (2H, m), 4.12 (3H, s), 6.36 (1H, d), 7.01 (1H, d), 7.26 (1H, m), 7.46 (1H, m), 7.600 (1H, s), 7.602 (1H, s), 7.72 (1H, d), 7.83 (1H, s), 8.16 (1H, d), 8.48 (1H, t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.NN.O.Cl>C(O)CO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: OCCO
Product: O=C1Cc2cccc(F)c2N1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of 7-fluoro-1H-indole-2,3-dione (100 g, 0.606 mol) in ethylene glycol (500 mL) was added an aqueous hydrazine solution (54% wt, 73 g, 1.21 mol) dropwise over 30 minutes. The mixture was heated to 120° C. and stirred for 6 hours. The mixture was cooled to room temperature and water (500 mL) was added. Concentrated hydrochloric acid (HCl; 60 mL) was added, the mixture was warmed to about 35 to about 40° C., and the mixture was stirred for 1 hour. The mixture was then cooled to about 0 to about 5° C. The solid compound was filtered, washed with cold water and dried at 55° C. under vacuum to give an off-white solid (76 g) in 83% yield with 96% HPLC purity.
Reaction SMILES: COC1C=CC2CC(C3C=CC=CC=3N)CCCC=2C=1.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH2:64]3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH2:64]3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CCCC(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: COc1ccc2c(c1)CCCC(c1ccccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1CCCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (477 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (431 mg). This compound (429 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (371 mg).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])OCC)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C(O)C.[CH2:20](N)[CH2:21][NH2:22]>CCOCC>[CH2:20]1[NH:11][C:7](=[C:6]2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3](=[O:2])[CH:13]=[CH:12]2)[NH:22][CH2:21]1
Reactant: CCOC(=N)c1ccc(O)c([N+](=O)[O-])c1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C1C=CC(=C2NCCN2)C=C1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of the imidate ester HCl 34 (650 mg, 2.63 mmol) in abs. ethanol was added ethylenediamine (0.53 ml, 7.89 mmol) at 0° C. and the mixture was stirred for 16 hrs at room temperature. Ether was added and the resulting precipitates were collected by filtration and dried in vacuo to give 490 mg (90% yield) of the desired cyclic amidine 35. 1H NMR (600 MHz, DMSO-d6) δ 8.38 (d, 1H, J=3 Hz), 7.45 (dd, 1H, J=9, 2.4 Hz), 3.79 (s, 4H).
Reaction SMILES: C([O:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)[C:6]1=[O:23])C=C.BrCC1C=CC=CC=1[Cl:32]>>[Cl:32][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:7]1[C:8]2[CH:14]=[CH:13][S:12][C:9]=2[C:10](=[O:11])[N:5]([OH:4])[C:6]1=[O:23]
Reactant: C=CCOn1c(=O)c2sccc2n(Cc2cccc(Br)c2)c1=O
Reactant: Clc1ccccc1CBr
Product: O=c1c2sccc2n(Cc2ccccc2Cl)c(=O)n1O

Procedure:
3-Allyloxy-1-(3-bromo-benzyl)-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) was alkylated with 1-bromomethyl-2-chloro-benzene via general procedure B2. The crude intermediate was deprotected via general procedure D2. The final product was purified by mass triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.65 (bs, 1H), 8.10 (d, 1H, J=5.1 Hz), 7.52 (dd, 1H, J=1.5, 7.8 Hz), 7.32 (dt, 1H, J=1.5, 7.5 Hz), 7.25 (dt, 1H, J=1.5, 7.5 Hz), 7.13 (d, 1H, J=5.4 Hz), 6.96 (dd, 1H, J=1.5, 7.5 Hz), 5.31 (s, 2H); Electrospray MS: 309 (M+H); retention time: 2.31 min.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: OCC1CCNCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCC(CO)CC1
Yield: 12.1 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and 4-piperidinemethanol (131 mg, 1.14 mmol) were reacted as described in Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea as a colorless solid (28 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (brs, 1H), 9.04 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.26-7.52 (m, 5H), 6.49 (s, 1H), 4.41 (m, 1H), 4.27 (m, 2H), 3.99 (s, 3H), 3.24 (m, 2H), 2.96-3.00 (m, 2H), 2.74-2.78 (m, 2H), 1.99-2.06 (m, 2H), 1.61-1.65 (m, 2H), 1.27 (s, 9H), 1.00-1.15 (m, 2H); LC-MS (ESI) m/z 607 (M+H)+.