Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=O)[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 3-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=3Cl)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C(C(F)(F)F)=CC=CC=1N1CCC(O)C1.FC(F)(F)C1C=C(N2CCC(O)C2)C=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)[CH2:13]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(c3cccc(C(F)(F)F)c3Cl)C2)cc1
Agent: OC1CCN(c2cccc(C(F)(F)F)c2)C1
Agent: OC1CCN(c2cccc(C(F)(F)F)c2Cl)C1
Product: Cc1ccc(S(=O)(=O)OC2CCN(c3cccc(C(F)(F)F)c3)C2)cc1

Procedure:
A mixture of 1-[2-chloro-3-(trifluoromethyl)phenyl]pyrrolidin 3-yl 4-methylbenzenesulfonate and 1-[3-(trifluoromethyl)phenyl]pyrrolidin-3-yl 4-methylbenzenesulfonate was obtained as white crystals (3.35 g, yield 69%) from a mixture of 1-[2-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-ol and 1-[3-(trifluoromethyl)phenyl]pyrrolidin-3-ol obtained in Reference Example 26 by a method similar to that in Reference Example 24. This was used for the next reaction without performing further purification.
Reaction SMILES: [N:1]#[C:2]Br.[N:4]#[C:5]Br.CC(C)=[O:9].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>CC(C)=O.O>[O-:9][C:2]#[N:1].[O-:11][C:5]#[N:4].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)([CH3:20])[CH3:19])=[CH:16][CH:17]=1
Reactant: N#CBr
Reactant: CC(C)=O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: N#C[O-]
Reaction time: 0.08 h

Procedure:
A quantity of 222.45 grams (2.10 moles) of cyanogen bromide was added to a reactor containing 350 milliliters of stirred acetone under a nitrogen atmosphere. The cyanogen bromide-acetone solution was cooled to -5° C., then 228.30 grams (1.0 mole) of Bisphenol A dissolved in 700 milliliters of chilled acetone was added to the reactor. The stirred solution was allowed to equilibrate at -5° C., then 203.39 grams of triethylamine (2.01 moles) was added to the reactor over a 24-minute (1440 s) period and so as to maintain the reaction temperature at -5° C. to 0° C. After completion of the triethylamine addition, the reactor was maintained at -11° to 1° C. for 40 minutes (2400 s), followed by addition of the reaction product to 3600 milliliters of chilled water with agitation. After 5 minutes (300 s), the water and product mixture was multiply extracted with methylene chloride. The combined methylene chloride extracts were sequentially washed with dilute 5 percent hydrochloric acid, water, dilute hydrochloric acid, water and then dried over anhydrous magnesium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum. Bisphenol A dicyanate, 265.5 grams, was recovered in 95.4 percent yield as a light tan colored crystalline solid. Infra-red spectrophotometric analysis confirmed the product structure.
Reaction SMILES: C([O:5][C:6](=[O:44])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[C:39]([Cl:40])=[CH:38][C:37]([Cl:41])=[C:36]([O:42][CH3:43])[C:33]=4[C:34]=3[CH3:35])=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[Cl:41][C:37]1[CH:38]=[C:39]([Cl:40])[C:32]2[O:31][C:30]([C:28]([NH:27][C:24]3[CH:23]=[CH:22][C:21]([C:18]4[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@@H:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:44])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=4)=[CH:26][CH:25]=3)=[O:29])=[C:34]([CH3:35])[C:33]=2[C:36]=1[O:42][CH3:43]
Reactant: COc1c(Cl)cc(Cl)c2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(Cl)cc(Cl)c2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To 102 mg of (S)-2-{4′-[(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 3 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with ether/chloroform. Filtration of the suspension gave 67 mg (72% yield) of (S)-2-{4′-[(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.9 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 3.9 (s, 3 H) 7.8 (m, 5 H) 7.9 (m, 2 H) 7.9 (d, J=8.6 Hz, 2 H) 8.1 (d, J=9.6 Hz, 1 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:11]([CH2:12][C:13]2[CH:31]=[CH:30][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])=[CH:35][CH:34]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 4-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].ClCCl.O.[CH3:21][N:22]1[CH2:27][CH2:26]N[CH2:24][CH2:23]1>Cl.CN1CCNCC1>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C:9]=2[CH:8]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C

Procedure:
2-(2-Aminoanilino)-5-methylthiophene-3-carbonitrile (10.0 g) is taken in N-methyl-piperazine (60 ml) and N-methyl-piperazine hydrochloride (24 gm). The solution is heated at 120° C. until completion of reaction. The reaction mass is cooled and dichloromethane (100 ml) and water is added. The mixture is cooled up to room temperature and dichloromethane layer is separated. 50 ml dichloromethane is evaporated and cyclohexane is added in clear solution. On Cooling the solution, solid is separated out, which is filtered and dried under vacuum to get Olanzapine Form I. (Purity >99.6%)
Reaction SMILES: [Cl:1][C:2]1[C:9](I)=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].[NH4+].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Cl:1][C:2]1[C:9]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(I)c1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Temperature: 50 °C
Reaction time: 41 h
Yield: 91 %

Procedure:
A thick-walled glass pressure vessel was charged with 2-chloro-4-fluoro-3-iodobenzonitrile (2.815 g, 10.00 mmol), Pd(PPh3)2Cl2 (0.351 g, 0.500 mmol), and CuI (0.095 g, 0.500 mmol) and sealed with a rubber septum. Anhydrous THF (25 mL) and DIPA (4.22 mL, 30.0 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic cleaning bath. To the degassed mixture was added ethynyltrimethylsilane (4.24 mL, 30.0 mmol), the vessel was resealed with a PTFE bushing, and the mixture was stirred in a heating block at 50° C. After 41 h, the mixture was cooled and poured into half-satd NH4Cl. The whole was filtered through a pad of Celite and the filtrate was extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (2.29 g, 91% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=8.7, 5.4 Hz, 1H), 7.12 (dd, J=8.7, 7.9 Hz, 1H), 0.30 (s, 9H); MS (GCMS EI) m/z 251 ([M]+, 14%), 236 ([M-CH3]+, 100%).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].[Mg].Cl>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C=CC(C)(C)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: COC(=O)CCC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of methyl 4-methyl-4-phenyl-2-pentenoate (0.3 g) in absolute methanol (10 ml) was added metallic magnesium ribbons (0.36 g) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 10% hydrochloric acid and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 0.30 g of methyl 4-methyl-4-phenylpentanoate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:4]=1[NH2:5].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[OH:1][CH2:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:4]=1[NH:5][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc(N)c(CO)c1
Product: CCOC(=O)C(=CNc1ccc(C)cc1CO)C(=O)OCC
Temperature: 110 °C
Yield: 87 %

Procedure:
A mixture of 2-(hydroxymethyl)-4-methylaniline (10.0 g) and diethyl ethoxymethylenemalonate (18.5 g) is heated at 110° C. for 1 h. Crystallization from ether/hexane afforded 19.5 g of the title compound. Physical characteristics: M.p. 92-95° C.; Anal. Found: C, 62.49; H, 6.88; N, 4.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[N:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][CH:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:41][C:38]4[CH:39]=[CH:40][N:35]=[CH:36][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate (Intermediate AAAAAA; 1.0 g, 1.935 mmol), pyrimidin-4-amine (0.193 g, 2.032 mmol), and THF (19.35 ml) and cooled to 0° C. LHMDS (1.0M in THF) (4.06 ml, 4.06 mmol) was added drop wise and the reaction was stirred for 30 minutes. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 80 g, gradient elution 0-10% MeOH:DCM) to afford 4-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=13.28 (br. s., 1H), 9.46 (s, 1H), 8.57 (t, J=1.0 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H), 8.22 (d, J=6.5 Hz, 1H), 8.03 (dd, J=1.9, 8.8 Hz, 1H), 7.83 (d, J=8.7 Hz, 3H), 7.47 (d, J=8.1 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.25 (dd, J=2.0, 8.1 Hz, 1H), 7.00 (d, J=6.7 Hz, 1H), 3.72 (s, 3H). m/z (ESI) 428.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([C:27]2[N:31](COCC[Si](C)(C)C)[C:30]3[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=3[N:28]=2)([N:24]([CH3:26])[CH3:25])[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(N(C)C)C)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2>>[CH3:1][C:2]1[C:3]([C:22]([C:27]2[NH:31][C:30]3[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=3[N:28]=2)([N:24]([CH3:26])[CH3:25])[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)N(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)N(C)C)c(C)cc(C)c32)cc1
Product: Cc1cc(C)c2[nH]ccc2c1C(C)(c1nc2cc(C#N)ccc2[nH]1)N(C)C

Procedure:
The title compound was synthesized from a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-(dimethylamino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-(dimethylamino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 102-B and 64-C. 1H NMR (400 MHz, CD3OD) δ ppm 7.56-8.08 (br. m, 2H), 7.55 (m, J=8.15, 1.20 Hz, 1H), 7.03 (d, J=3.23 Hz, 1H) 6.72 (s, 1H) 6.28 (d, J=3.23 Hz, 1H) 2.43 (s, 3H) 2.23 (s, 3H) 2.06 (s, 3H) 2.05 (s, 3H). HRMS calcd. for C23H26N5 (M+H)+ 358.2026. found 358.2010.
Reaction SMILES: [C:1]([C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29]>>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]([CH:31]([CH3:33])[CH3:32])[C:28]([O:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:14]=1)=[O:29]
Reactant: O=C(c1ccccc1)c1cccc(CO)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Product: CC(C)C(C(=O)OCc1cccc(C(=O)c2ccccc2)n1)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 3, (6-benzoyl-2-pyridyl)methanol and 2-(2-naphthyl)-3-methylbutanoic acid are reacted, yielding (6-benzoyl-2-pyridyl)methyl 2-(2-naphthyl)-3-methylbutanoate.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[N+:13]([C:16]1[C:17]([NH2:23])=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>CC#N>[N+:13]([C:16]1[C:17]2[NH:23][C:5](=[O:11])[NH:22][C:18]=2[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CC#N
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C

Procedure:
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3-nitro-1,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0° C. and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: m/z=180 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:35]#[C:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)c1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (9.25 mg, 6%); 1H NMR δ (CDCl3): 7.92 (d, J=7.92 Hz, 1H), 7.4-7.17 (m, 13H), 5.5 (s, 2H); LCMS m/z: 308.
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[N:11]1[CH2:27][CH2:26][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][NH:16][C:15]2=[O:25])[CH2:13][CH2:12]1.[CH3:28]I>>[ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[N:11]1[CH2:12][CH2:13][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][N:16]([CH3:28])[C:15]2=[O:25])[CH2:26][CH2:27]1
Reactant: CI
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1Cc3ccccc3C1)CC2
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3Cc4ccccc4C3)CC2)C1=O

Procedure:
The title compound, m.p.>250° C. and MS: m/e=362.2 (M+H+) was prepared in accordance with the general method of example 4 from 8-indan-2-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (1:1) and methyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[Br:30][C:31]1[S:35][C:34]([C:36]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(Br)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-bromothiophene-2-carboxylic acid (44.4 mg, 0.21 mmol)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:20][C:21]4[N:22]([C:24]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([Cl:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[Cl:27][C:25]1[N:26]=[C:21]2[CH:20]=[C:19]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[N:23][N:22]2[C:24]=1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(-c5ccc(F)cc5)c(Cl)nc4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nn4c(-c5ccc(F)cc5)c(Cl)nc4cc3-c3ccccc3)cc2)CCC1

Procedure:
12.1 mg (0.98 mmol) (1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester in 1 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a ForaPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH3 yielding 9.8 mg (93.4%) of the title compound.
Reaction SMILES: [CH2:1]1COCC1.[C:6]([N:16]=[C:17]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O>CO>[CH3:1][O:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])=[N:16][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: O=C(O)CCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Product: COC(=O)CCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a 0° C. THF (700 mL) solution of compound 1 (133 g, 0.3 mol) was added carbonyldiimidazole (55.3 g, 0.34 mol). After the addition was complete, the resultant solution was allowed to warm to room temperature and stirred for 45 min. Anhydrous methanol (100 mL) was added. The solution was stirred for 16 h and concentrated. The residue was triturated with ether (400 mL). The supernatant was separated. The process was repeated with two more portions of ether (2×200 mL). The ether phases were combined, washed with H2O, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (Et2O:hexane/1:1) to afford 130 g (95%) of the title product, mp 36°-39° C.