Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:29])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
Dissolve 2 gm (0.0071 moles) of the ester of Example 2 in 200 cc of chloroform and 1.396 gm of m-chloroperbenzoic acid and stir at room temperature for 20 minutes. Add successive 100 mg portions of m-chloroperbenzoic acid until thin layer chromatography slows conversion of the starting material. Basify with calcium hydroxide and separate the solids. Chromotograph the solids over silica gel eluting with 30% ethyl acetate in benzene to obtain the title product (yield 870 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([C:23](O)=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23]([CH:19]3[O:20][CH2:21][CH2:22][N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:18]3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A mixture of 4-chlorobenzene-1,2-diamine (2.0 g, 14.03 mmol) and 4-benzylmorpholine-2-carboxylic acid (4.66 g, 21.04 mmol) in polyphosphoric acid (20 mL) was stirred at 140° C. overnight. The reaction mixture was cooled to room temperature and treated with 100 mL of water. The aqueous phase was adjusted to weakly basic with 2 N aqueous sodium hydroxide and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give the crude product as a off-white solid. The residue was triturated with hex/EtOAc (1×25 mL). The resulting solid was filtered, rinsed with n-hexane, and collected. The solvent was evaporated in vacuo to afford the title compound (2.1 g). LC-MS (ES) m/z=328 [M+H]+.
Reaction SMILES: [CH:1](=[N:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[Cl:10][CH:11]([Cl:15])[C:12](Cl)=[O:13].C(OCC)C>C(N(CC)CC)C>[C:6]([N:5]([CH:1]=[CH:2][CH2:3][CH3:4])[C:12](=[O:13])[CH:11]([Cl:15])[Cl:10])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCCC=NC(C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC=CN(C(=O)C(Cl)Cl)C(C)(C)C

Procedure:
In a similar procedure as Example I, 6.6 g. (0.052 mole) N-butylidene-t-butylamine was reacted with 4.8 ml. (0.05 mole) dichloroacetyl chloride in 100 ml. diethyl ether and 7.2 ml. triethylamine. There was obtained 9.3 g. of the title compound, an oil, nD30 = 1.4858.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:24][NH2:25]>CCO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:24][NH2:25])[NH2:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: CCO
Solvent: O
Product: NN=C(N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 60 °C

Procedure:
To a solution of 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbonitrile (80 mg, 0.278 mmol) in EtOH (3 mL), was added hydrazine hydrate (18.12 mg, 0.362 mmol). The reaction was heated to 60° C. overnight. The mixture was filtered and washed with EtOH, H2O, and EtOH to give a yellow solid. 1H-NMR (400 MHz, DMSO-d6+D2O) δ ppm 9.29 (s, 1H), 8.88 (s, 1H), 8.34 (d, 1H), 8.01 (m, 2H), 7.83 (d, 1H), 7.52 (m, 1H), 6.16 (s, 2H). LCMS (method B): [MH]+=320, tR=1.03 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O.Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=[C:29]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:28]=1>C(#N)C>[C:41]1([NH:40][C:29]2[N:30]=[C:31]([NH:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:32]=[C:27]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[N:28]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Clc1nc(Nc2ccccc2)nc(Nc2ccccc2)n1
Reactant: NCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: Fc1ccc(CNc2nc(Nc3ccccc3)nc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A 7.5 mg (60 μmol) portion of p-fluorobenzylamine and 52 μl of diisopropylethylamine were added to a mixed solution of 400 μl of acetonitrile and 120 μl of N-methylpyrrolidone containing 8.9 mg (30 μmol) of 6-chloro-N,N′-diphenyl-1,3,5-triazine-2,4-diamine and stirred at 80° C. for 3 hours. The reaction solution was filtered and then injected into a fractional LC-MS apparatus to collect a fraction containing the desired molecular weight. By evaporating the solvent, 6.1 mg (yield 45%) of N,N′-diphenyl-N″-(4-fluorobenzyl)-1,3,5-triazine-2,4,6-triamine was obtained. A retention time of 2.77 minutes and a purity of 93% were determined by an analytical LC-MS.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)[CH:7]=[C:6]([Br:17])[CH:5]=1.[H-].[Na+].O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:7]=[C:6]([Br:17])[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(NC(=O)CCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 3-bromo-5-(4-chloro-butanoylamino)-benzoic acid methyl ester (D13) (530 mg, 1.6 mmol, 1 equiv) in THF (5 ml) at room temperature was added NaH (60% in mineral oil, 64 mg, 1.7 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature for 2 h. H2O was then added and the resulting mixture was diluted with AcOEt. The two layers were separated and the organic phase dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D9a) (361 mg, 76%) as a yellow solid. [M−H]-296.3, RT=2.49.
Reaction SMILES: [Cl:1][C:2]1C=[CH:9][C:8]([N:11]([CH3:28])[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[C:24]([F:27])([F:26])[F:25])=[O:13])=[CH:7][C:3]=1C(O)=O.CN(C)C=O.[C:34](Cl)(=O)[C:35]([Cl:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:7][C:8]([N:11]([CH3:28])[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[C:24]([F:25])([F:26])[F:27])=[O:13])=[CH:9][C:34]=1[C:35]([Cl:37])=[O:36]
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150.0 mg (0.29 mmol) of 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoic acid are suspended in 5.0 ml of dichlormethane p.a. 0.02 ml of N,N-dimethylformamide p.a. and 0.075 ml (0.86 mmol) oxalyl chloride are then added successively to the suspension. The reaction mixture is stirred at room temperature for 0.5 h and then heated under reflux for 40 minutes. The solvent is removed under reduced pressure on a rotary evaporator. The 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoyl chloride formed is used for the subsequent synthesis step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([O:26]C)=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:8]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:8]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3ccsc3)[nH]c3cc(OC)ccc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccsc3)[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of methyl 6-(6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (936 mg) in tetrahydrofuran/methanol (14.7 mL/6.3 mL) was added 2 mol/L aqueous sodium hydroxide solution (3.71 mL) at room temperature, and this mixture was stirred at 60° C. for 2 hours. The reaction mixture was left to be cooled and concentrated under reduced pressure. The residue was suspended in water (30 mL) and the resulting mixture was acidified by the addition of 1 mol/L hydrochloric acid (7.8 mL). After stirring at room temperature for 1 hour, the precipitate was collected by filtration, washed with water, and then dried under reduced pressure. The suspension of the solid in ethanol was heated under reflux to give a solution. The solution was left to be cooled. The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (547 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.37 (2H, s), 6.64 (1H, dd, J=2.3, 8.8 Hz), 6.85 (1H, d, J=2.3 Hz), 7.37 (1H, dd, J=1.5, 7.3 Hz), 7.42 (1H, d, J=8.8 Hz), 7.57 (1H, dd, J=1.3, 5.0 Hz), 7.67 (1H, dd, J=2.8, 5.0 Hz), 7.77-7.88 (2H, m), 8.09 (1H, dd, J=1.3, 2.8 Hz), 11.13 (1H, s), 12.60-13.70 (1H, br).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[Cl:28][CH2:29][C:30]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:31]
Reactant: Cc1ccc(C(F)(F)F)cc1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-trifluoromethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-trifluoromethylanilino)-acetaldehyde.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:13]>>[Br:13][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCCCCC1CCCCC1
Product: BrCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 195.2 %

Procedure:
4-Cyclohexyl-butan-1-ol(8.1 ml, 47 mmol) at -5° C. under nitrogen was treated dropwise over 10-15 min with 2.2 ml (23 mmol) of phosphorus tribromide, stirred at 0° C. for 15 min, room temperature for 2 h, then at 100° C. for 1.5 h before cooling to 0° C. The reaction was quenched with 50 g of ice, diluted with 100 ml of brine, and extracted with ether. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and distilled at 2 mm Hg, 100° C., to give 9.84 g (96%) of 1-bromo-4-cyclohexylbutane as a colorless liquid. NMR (CDCl3, TMS) δ 0.6-2.3 (m, 17H), 3.43 (t, J=7 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1.Br[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]3=[N:21][CH:20]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccc(F)cn2)c1
Product: Fc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)nc1

Procedure:
4-Fluoro-3-(5-fluoropyridin-2-yl)phenylboronic acid was coupled with 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 3.5% methanol, then crystallisation from hot toluene/isohexane and further crystallisation from hot methanol, gave 3-[4-fluoro-3-(5-fluoropyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 9.28 (1H, d, J 7), 8.76 (1H, d, J 3), 8.30 (1H, s), 8.20 (1H, dd, J 7 and 2), 7.88 (3H, m), 7.62 (1H, dd, J 11 and 9), 7.53 (1H, d, J 7).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4](O)[CH:3]=1.[Cl-:14].[Cl-:15].[Ca+2].C(Cl)Cl>O(Cl)Cl.[P+5].O>[Cl:14][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:15])[CH:3]=1
Reactant: CCOC(=O)c1cnc(O)cc1O
Reactant: [Cl-]
Agent: ClOCl
Agent: [Ca+2]
Agent: [P+5]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
(Wallace, E., et. al., ibid.) A stirred suspension of compound ii (1.40 g, 7.67 mmol) in phosphorus (V) oxychloride (15 mL) was heated to 110° C. for 2.5 h with a guard tube (CaCl2) fitted. The reaction mixture was cooled to room temperature, reduced in vacuo and the resulting dark brown residue taken up in a small volume of DCM (˜5 mL) and transferred dropwise onto a slurry of ice in water (250 mL) whilst stirring vigorously. The aqueous mixture was extracted with EtOAc (3×100 mL), the organic extracts combined, dried (MgSO4) and evaporated to dryness to afford the crude product as an orange gum. Column chromatography (SiO2), eluting with 15:1 Hexanes-EtOAc, afforded compound iii. (1.33 g, 6.14 mmol, 79%) as a colourless oil; [M+H]+ m/z=220.0.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:33]([CH3:34])=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]4)[N:18]=3)[S:16][C:12]=2[C:11]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[O:42]1CC(N2CCNCC2)C1>>[C:1]([O:5][C@@H:6]([C:10]1[C:33]([CH3:34])=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]5[CH2:30][O:42][CH2:31]5)[CH2:25][CH2:24]4)[N:18]=3)[S:16][C:12]=2[C:11]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CN(C2COC2)CCN1
Reactant: Cc1cc2nc(-c3cccc(N4CCN(C(C)C)CC4)n3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3cccc(N4CCN(C5COC5)CC4)n3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-6-yl)acetic acid was prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid, except using 1-(oxetan-3-yl)piperazine instead of 1-isopropylpiperazine. LCMS-ESI+: calc'd for C32H36ClN4O4S: 607.2 (M+H+); Found: 607.2 (M+H+); 1H NMR (400 MHz, CD3OD): δ 7.70-7.81 (m, 3H), 7.64 (m, 1H), 7.49-7.56 (m, 3H), 7.04 (d, J=8 Hz, 1H), 5.19 (s, 1H), 4.88 (br m, 2H), 4.77 (br m [under solvent], 4H), 4.35 (m, 1H), 3.80 (br m, 2H), 3.24 (m, [under solvent] 4H), 0.93 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccc(F)c(F)c1
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Cl)cnn1C
Yield: 36.4 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (30 mg, 0.13 mmol) was treated with 3,4-Difluorophenyl isocyanate (17 μL, 0.14 mmol) in a similar manner to Example 1.53, providing 18.6 mg (34%) of Compound 92: LCMS m/z (%)=393 (M+H35Cl, 100), 395 (M+H37Cl, 38). 1H NMR (400 MHz, acetone-d6) δ: 8.18 (s, 1H), 8.05 (s, 1H), 7.65 (m, 1H), 7.57 (dd, J1=8 Hz, h=4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=2 Hz, 1H), 7.09 (d, J=4 Hz, 1H), 7.06 (d, J=2 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.55 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=O)[CH:12]=[C:6]2[C:5]=1[NH:22][C@@H:23]([CH:25]1[CH2:27][CH2:26]1)[CH3:24])(=[O:3])[NH2:2].[CH3:28][NH:29][CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:25]1([C@H:23]([NH:22][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:21]=[CH:20][CH:19]=[C:15]([C:16](=[O:18])[N:29]([CH3:30])[CH3:28])[CH:14]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH3:24])[CH2:26][CH2:27]1
Reactant: CNC
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(C(=O)O)c3)cc12)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(C(=O)N(C)C)c3)cc12)C1CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of (R)-3-(3-carbamoyl-4-(1-cyclopropylethylamino) pyrrolo[1,2-b]pyridazin-6-yl)benzoic acid (Example 85, 15 mg, 0.041 mmol), dimethylamine (0.021 mL, 0.041 mmol) and triethylamine (8.61 μl, 0.062 mmol) in DMF (0.5 mL) was added BOP (18.21 mg, 0.041 mmol) which was stirred at 23° C. for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (5.7 mg, 35%). HPLC (condition H): retention time=1.47 minutes. LC/MS (M+H)+=392.3. 1H NMR (500 MHz, MeOD) δ ppm 8.06 (1 H, s), 7.86 (1 H, d, J=1.9 Hz), 7.67-7.71 (1 H, m), 7.64 (1 H, t, J=1.4 Hz), 7.45 (1 H, t, J=7.6 Hz), 7.24-7.27 (1 H, m), 7.09 (1 H, d, J=1.7 Hz), 4.01-4.09 (1H, m), 3.13 (3 H, s), 3.04 (3 H, s), 1.44 (3 H, d, J=6.4 Hz), 1.09-1.18 (1 H, m), 0.57 (2H, dd, J=13.5, 8.7 Hz), 0.34-0.41 (2 H, m).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])C1C=CC=CC=1.CCN(C(C)C)C(C)C>CO.[Pd]>[F:19][C:16]([F:17])([F:18])[CH2:15][O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: FC(F)(F)COC[C@@H]1CCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)COC[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of (S)-1-benzyl-2-(2,2,2-trifluoroethoxymethyl)-pyrrolidine (0.5 g, 1.83 mmol) in MeOH (20 mL) was added Hunig's base (1.18 g, 9.15 mmol). The flask was purged three times with Ar and 10% Pd/C (0.487 g, 0.457 mmol) was added to the mixture. The flask was purged three times with hydrogen and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a pad of Celite, washed with MeOH (20 mL) and the resulting solution was concentrated in vacuo to give the title compound (0.250 g, 75%) as a colorless semi-solid. MS: 184.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.O.CO.C(O)C>C(#N)C.O1CCOCC1.CN(C)C=O.C(C(C)=O)C.CC(C)=O.CC(O)C>[CH3:8][C:6]1([CH3:9])[CH2:5][C:4](=[O:10])[CH2:3][C:2](=[O:1])[CH2:7]1
Reactant: CC1(C)CC(=O)C=C(O)C1
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(=O)C1
Temperature: 45 °C

Procedure:
A mixture of 3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (dimedone), and R1 -thiolsulfonate, an alkali metal hydroxide, water and a water-miscible solvent, i.e., methanol, ethanol, 2-propanol, acetone, methyl ethyl ketone, dimethylformamide, dioxane or acetonitrile, is heated with stirring at any temperature between about 45°C. and the boiling temperature of the aqueous solvent (preferably at the boiling temperature) for a period of time of about one hour to about 48 hours (preferably three to 24 hours). After the reaction, the solvent mixture is removed by evaporation or by distillation. The residue is washed with water to remove the sulfinate salt by-product, and the crude product is collected on a filter and dried. Purification is accomplished by recrystallizing the crude product from an organic solvent, i.e., a hydrocarbon or lower alkanol such as benzene, cyclohexane, n-hexane, methylcyclohexane, n-pentane, ethanol, aqueous ethanol, methanol, aqueous methanol or toluene or a combination thereof.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C:5]#[C:6][CH:7]([OH:18])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[C:5]#[C:6][C:7](=[O:18])/[CH:8]=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOC(C#CC(O)/C=C/c1ccc(OC)cc1)OCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C#CC(=O)/C=C/c1ccc(OC)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.0 g (10.33 mmol) of (E)-6,6-diethoxy-1-(p-methoxyphenyl)-1-hexen-4-yn-3-ol in 15 ml of methylene chloride was added at 0° to a suspension of 27 g of manganese dioxide in 45 ml of methylene chloride. The reaction mixture was subsequently stirred at room temperature for a further 1 hour, filtered over magnesium sulphate and evaporated. The residue was chromatographed on 100 g of silica gel with petroleum ether/ether (2:1), whereupon (E)-6,6-diethoxy-1-(p-methoxyphenyl)-1-hexen-4-yn-3-one was obtained as a light yellowish oil.
Reaction SMILES: [Cl:1][C:2]([Cl:31])([Cl:30])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[O:14][CH:13]=[C:12]([CH:27]=[O:28])[C:11]2=[O:29])=[O:6].S(=O)(=O)([OH:34])N.Cl([O-])=O.[Na+]>ClCCl.O>[Cl:31][C:2]([Cl:1])([Cl:30])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[O:14][CH:13]=[C:12]([C:27]([OH:34])=[O:28])[C:11]2=[O:29])=[O:6]
Reactant: O=Cc1coc2cc(OC(=O)OCC(Cl)(Cl)Cl)c(OC(=O)OCC(Cl)(Cl)Cl)cc2c1=O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Temperature: 10 °C
Yield: 79.4 %

Procedure:
The compound (838.4 mg) obtained in Example 4, (b) was dissolved in 16 ml of dichloromethane, and with stirring at 10° C., a solution of 525 mg of sulfamic acid in 9.5 ml of water was added, followed by addition of a solution of 262.8 mg of sodium chlorite in 0.6 ml of water. The mixture was stirred for 1 hour at the same temperature. The reaction mixture was allowed to separate. The dichloromethane layer was washed with water and then with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl ether to afford 685 mg of the desired product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:31]>>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=[N:7]1)[CH3:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2ccnnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2ccnnc2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 4.5 g (16.2 mmol) of the compound of Example 79A and 3.86 g (17.8 mmol) of 2-bromo-4-nitrotoluene gave, after 3 h of heating under reflux, a crude product which was purified by chromatography on a Biotage system (100 g Snap column; mobile phase gradient ethyl acetate/0-8% methanol). This gave 5.52 g (82% of theory) of the title compound.