Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=1.[H-].[Na+].O.CN([CH:37]=[O:38])C>>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH2:20][CH2:21][C:25]([O:38][CH3:37])([CH3:26])[CH3:29])[C:12]2=[O:16])=[O:10])[CH:7]=1
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCNC4=O)cc3Cl)ccn2)cn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(C)(C)CCN1CCN(C(=O)Nc2cc(Cl)c(Oc3ccnc(-c4cnn(C)c4)c3)cc2F)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A 0° C. solution of Example C9 (0.350 g, 0.812 mmol) in DMF (5 mL) was treated with NaH (60% in mineral oil, 0.100 g, 2.50 mmol), stirred at RT for 0.5 h, treated with Example C4 (0.500 g, 1.836 mmol) and stirred at RT overnight. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxy-3-methylbutyl)-2-oxoimidazolidine-1-carboxamide (128 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.38 (m, 2 H), 8.26 (s, 1 H), 7.97 (d, J=0.7 Hz, 1 H), 7.57 (d, J=11.3 Hz, 1 H), 7.20 (d, J=2.5 Hz, 1 H), 6.64 (dd, J=5.7, 2.5 Hz, 1 H), 3.84 (s, 3H), 3.80 (m, 2 H), 3.48 (t, J=8.2 Hz, 2 H), 3.28 (m, 2 H), 3.09 (s, 3 H), 1.70 (m, 2 H), 1.11 (s, 6H); MS (ESI) m/z: (M+H+): 531.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([O-:11])[CH:3]=1.[Na+].[C:13]([O-])([O-])=O.[K+].[K+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([O:11][CH3:13])[C:5]([C:9]#[N:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(N)cc([O-])c1C#N
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(N)nc(C)c1C#N
Reaction time: 216 h

Procedure:
To a mixture of sodium 6-amino-3-cyano-2-methylpyridin-4-olate (500 mg, 2.92 mmol, prepared in analogy to WO2001062233A2 and isolated as sodium salt), and K2CO3 (808 mg, 5.84 mmol) in DMF (1 ml) was added MeI (0.200 ml, 3.21 mmol), and the reaction mixture was stirred at it for 9 d. Saturated NaHCO3 (50 ml) was added and the mixture was extracted with EA (4×20 ml). The combined organic extracts were diluted with additional DCM and MeOH until homogeneous, dried over Na2SO4, filtered and concentrated. The crude product was recrystallized from refluxing MeOH-DCM to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.34 (s, 3H), 3.82 (s, 3H), 5.91 (s, 1H), 6.83 (br, s, 2H); LCMS RtM=1.11 min, [M+H]+=164.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C(Cl)Cl>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:32]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCCC1
Reactant: O=C=Nc1ccccc1F
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccccc2F)ccc1OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A solution of 3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine (21.0 mg, 0.07 mmol) in methylene chloride (1 mL) was treated with 2-fluorophenyl isocyanate (0.074 mmol), then the reaction mixture stirred at room temperature overnight and concentrated to give an oily residue that was subjected to a purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) to afford Compound 65 as a white solid in 45.1% yield. LCMS m/z (%)=438.4 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.52 (bs, 1H), 8.32-8.28 (m, 1H), 8.02 (bs, 1H), 7.57 (dd, J=2.7, 8.9 Hz, 1H), 7.48 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.18-7.06 (m, 3H), 7.00-6.92 (m, 1H), 6.22 (d, J=1.8 Hz, 1H), 4.11-4.08 (m, 2H), 3.75 (s, 3H), 2.67-2.60 (m, 2H), 2.42-2.31 (m, 4H), 1.52-1.43 (m, 4H), 1.40-1.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C:26]1[N:31]=[C:30](Cl)[C:29]([C:33]#[N:34])=[C:28]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=2)[N:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C:26]1[N:31]=[C:30]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:29]([C:33]#[N:34])=[C:28]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=2)[N:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccccc1Cl
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc(Cl)c2C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc(Oc3ccccc3Cl)c2C#N)c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
o-Chlorophenol and 60% sodium hydride were added to a mixture of 2-[cis-2-(tert-butoxycarbonylamino)cyclohexylamino]-4-chloro-6-(3-methylanilino)pyrimidine-5-carbonitrile and DMF, followed by stirring at room temperature for 30 minutes and at 70° C. for 5 hours. Thereafter, purification in the usual way afforded 2-[cis-2-(tert-butoxycarbonylamino)cyclohexylamino]-4-(2-chlorophenoxy)-6-(3-methylanilino)pyrimidine-5-carbonitrile (colorless solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10]C(C)(O)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(O)C#Cc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cc(Cl)cc(Cl)c1
Reaction time: 3.5 h
Yield: 37 %

Procedure:
A mixture of 7.95 g (0.0655 mole) of 1-(3,5-dichlorophenyl)-3-methyl-1-butyn-3-ol and 30 g of sodium hydroxide in 150 ml of dry toluene was heated to reflux with stirring for 3.5 hours. The toluene was removed in vacuo to yield a brown solid residue. The residue was triturated with hexane and the resulting hexane solution washed with aqueous sodium thiosulfate solution. The hexane layer was separated and evaporated in vacuo to yield the crude product. Recrystallization from hexane yielded 4.15 g of pure product, mp 80°-81.5° C.
Reaction SMILES: Cl.[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[C:27]1([C:20]2[O:21][C:22]([C:23]([F:26])([F:24])[F:25])=[C:18]([C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([N:2]4[CH2:8][CH2:7][CH2:6][N:5]([CH2:34][C:35]5[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=5)[CH2:4][CH2:3]4)=[CH:10][CH:11]=3)=[O:17])[N:19]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(CN2CCCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (56 mg, 0.12 mmol), 4-bromomethyl-benzoic acid (28 mg, 0.13 mmol), triethylamine (0.07 mL, 0.50 mmol) in DMF (5 mL) was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of ethyl acetate and washed with 50 mL of saturated ammonium chloride, water (50 mL), and dried with anhydrous sodium sulfate. The solvent was removed and the residue was triturated with ethyl acetate, followed by filtration, to afford 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepan-1-ylmethyl)-benzoic acid as a yellow solid (20 mg, 29% yield) LCMS for C30H27F3N4O4 calcd. (m/e) 564, observed 565 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(Cl)(Cl)Cl)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:13]Cl>>[Cl:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: ClCl
Reactant: Clc1cnc(C(Cl)(Cl)Cl)c(Cl)c1
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
The batch chlorinator R1 was charged with 50 grams of starting material containing 90.4% 3,5-dichloro-2-trichloromethyl pyridine by weight, and chlorine was sparged through the reactor by means of sparger 14 for 15 hours at a reaction temperature of 170° C. Samples were taken at the time which corresponded to about 14% conversion of the 3,5-dichloro-2-trichloromethly pyridine. The yield of 2,3,5-trichloropyridine at this temperature, was about 14%, i.e., about half the yield of like runs at 200° C. (Table ONE). The chlorination was then continued under the same reaction conditions except at a temperature of 160° C. and yielded no appreciable quantity of 2,3,5-trichloropyridine in 8 hours. Analytical data with respect to this Example are presented in the following Table TWO:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([N:16]([CH2:26][C:27]([O:29]C)=[O:28])[CH2:17][CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:31])[NH:11][C:10](=[O:32])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([N:16]([CH2:26][C:27]([OH:29])=[O:28])[CH2:17][CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:31])[NH:11][C:10](=[O:32])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN(CC=Cc1ccccc1)C(=O)C1=C(C)NC(=O)NC1c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)N(CC=Cc2ccccc2)CC(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.220 mmol) of methyl [[4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl]-(3-phenyl-2-propene-1-yl)-amino]acetate was dissolved in 2 ml of methanol. 0.480 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was washed with water. After the slurry washing, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.CN(C)C=O.[S-2:25].[Na+].[Na+]>C(O)(=O)C>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([SH:25])=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Reactant: [S-2]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1ncc2c1ncc1c(S)nc3ncnn3c12
Reaction time: 1 h

Procedure:
5.6 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.) are dissolved in 100 ml. of dimethylformamide. 2 g. of powdered sodium sulfide are added and the mixture is stirred for 1 hour. After this time, the solution is carefully acidifed with acetic acid. 8-Ethyl-8H-pyrazolo[3',4':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-5-thiol precipitates and is filtered off.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([C:19]3[N:20](S(N(C)C)(=O)=O)[CH:21]=[C:22]([CH2:24][C:25]([CH3:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH2:27])[N:23]=3)([OH:18])[CH3:17])=[CH:11][CH:10]=2)=[N:7][CH:8]=1>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([C:19]3[NH:20][CH:21]=[C:22]([CH2:24][C:25]([CH3:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH2:27])[N:23]=3)([OH:18])[CH3:17])=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Agent: Cl
Solvent: CO
Product: C=CC(C)(Cc1c[nH]c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to an ambient temperature solution of 2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide (150 mg, 0.28 mmol) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed. Chromatography over silica eluting with 0-80% acetone/methylene chloride afforded the title compound. (M+H) found: 434.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(Cl)(=O)=O)=C[CH:2]=1.[Cl:12][C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([CH3:22])[CH:14]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.O>[Cl:12][C:13]1[N:18]=[C:17]([C:19]([O:21][C:1]([CH3:11])([CH3:6])[CH3:2])=[O:20])[CH:16]=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(Cl)nc(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: Cc1cc(Cl)nc(C(=O)OC(C)(C)C)c1
Reaction time: 22 h
Yield: 38.1 %

Procedure:
p-Toluenesulfonyl chloride (1.11 g, 5.83 mmol) was added to a solution of 6-chloro-4-methylpyridine-2-carboxylic acid (0.50 g, 27.6 mmol) as a known compound in tert-butyl alcohol (16.5 ml) and pyridine (2.4 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 22 hours. Thereafter, a solution of sodium hydrogen carbonate (1.22 g, 14.6 mmol) in water (33 ml) was added to the resulting solution, and the mixture thus obtained was then stirred. The solvent was distilled away from the reaction solution under reduced pressure. Water was added to the residue thus obtained, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure to obtain the title compound (0.506 g, yield: 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[NH2:23])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: Nc1cccc(B(O)O)c1
Product: CC(On1ccc2ncc(-c3cccc(N)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (3-aminophenyl)boronic acid according to the procedure described in example 4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[Cl:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.O1CCOCC1.C([Si](CC)(CC)[O:50][C@H:51]1[CH2:56][CH2:55][C@H:54]([N:57]2[CH2:61][CH2:60][C@:59]3([CH2:66][CH2:65][CH2:64][NH:63][CH2:62]3)[C:58]2=[O:67])[CH2:53][CH2:52]1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[N:63]1[CH2:64][CH2:65][CH2:66][C@@:59]2([C:58](=[O:67])[N:57]([C@H:54]3[CH2:53][CH2:52][C@H:51]([OH:50])[CH2:56][CH2:55]3)[CH2:61][CH2:60]2)[CH2:62]1
Reactant: CC[Si](CC)(CC)O[C@H]1CC[C@H](N2CC[C@]3(CCCNC3)C2=O)CC1
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCN(c1cc(C(F)(F)F)ccc1Cl)C2
Reaction time: 0.33 h

Procedure:
A mixture of 2-bromo-1-chloro-4-(trifluoromethyl)benzene (26 mg, 0.0001 mol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.000002 mol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (5 mg, 0.00001 mol) in 1,4-dioxane (0.5 mL, 0.006 mol) was stirred under N2 (g) for 20 min. To this mixture were added (5S)-2-{trans-4-[(triethylsilyl)oxy]cyclohexyl}-2,7-diazaspiro[4.5]decan-1-one (30 mg, 0.00008 mol) and sodium tert-butoxide (11.8 mg, 0.000123 mol), and the resulting mixture was degassed and stirred at 100° C. for 16 h. At this time 1M TBAF (tetra-n-butylammonium fluoride) in THF (0.3 mL) was added dropwise to the reaction mixture and the solution was stirred at rt for 1 h. The volatiles were removed in-vacuo and the residue was purified by prep-HPLC to afford the desired product. LC-MS: 431.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.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>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:5]2[C:6](=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Oc1ccc(Br)nc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.84 g (6.10 mmol) sample of 6-bromo-2-iodo-3-pyridinol, from step 28d above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.30 g, 0.4 mmol), CuI (0.3 g, 1.6 mmol) and triethylamine (1.2 mL, 8.5 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.3 g (6.7 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 5 mL of DMF, was added carefully. The reaction was stirred at 80° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 50% brine, and the extract was dried over MgSO4. The solvent was removed, and the residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 1.4 g of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.31(s, 9H), 1.89-2.06 (m, 3H), 2.27-2.34 (m, 1H), 3.43-3.5 (m, 2H), 4.96-5.0 (m, 1H), 6.72 (s, 1H), 7.38-7.41 (d, 1H, J=8.6 Hz), 7.83-7.86 (d, 1H, J=8.6 Hz); MS m/z: 367 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[S:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[C:18]([S:15](=[O:16])(=[O:17])[NH:13][CH2:12][C:8]2([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][CH2:11]2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)C1(CN)CCC1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(S(=O)(=O)NCC2(C(=O)OC(C)(C)C)CCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (step 2) (1.47 g, 7.38 mmol) in DCM (40 ml) was treated with TEA (2.57 ml, 18.44 mmol) followed by methyl 3-(chlorosulfonyl)benzoate (1.91 g, 8.11 mmol) and DMAP (0.09 g, 0.74 mmol). The mixture was stirred at RT for 2 h and then partitioned between DCM and water. The aqueous portion was extracted with DCM and the combined organic extracts were washed with 0.1N HCl, brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded the title compound as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 8.56 (1H, s), 8.27 (1H, d), 8.08 (1H, d), 7.64 (1H, t), 5.21 (1H, br t), 3.98 (3H, s), 3.20 (2H, d), 2.37 (2H, m), 1.96 (4H, m), 1.46 (9H, s).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:11]3)[C:4](=[O:24])[CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:45].Cl>>[ClH:45].[ClH:45].[CH2:25]([NH:32][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:11]3)[C:4](=[O:24])[CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: O=c1cc(O)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=c1cc(NCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Yield: 22 %

Procedure:
4-Hydroxy-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (120 mg, 0.37 mmol) and benzylamine (0.3 mL) were irradiated in a microwave tube for min at 300 W. Purification by column chromatography (12 g ISCO column eluting with ethyl acetate and a methanol/ammonia mixture (10:1); gradient 100% ethyl acetate to 80% ethyl acetate over 30 min at 25 mL/min) provided the free-base. This was converted to the dihydrochloride as in Example 64 to provide the title compound (43 mg, 22%) as a yellow solid: mp 180-185° C.; 1H NMR (500 MHz, CD3OD) δ 8.25 (s, 1H), 7.90 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.75 (s, 1H), 7.51-7.49 (dd, J=8.9, 1.9 Hz, 1H), 7.40-7.39 (m, 4H), 7.33-7.30 (dd, J=8.5, 4.3 Hz, 1H), 6.63 (d, J=76 Hz, 1H), 4.90 (t, J=5.9 Hz, 2H), 4.54 (s, 2H), 3.86 (t, J=5.9 Hz, 2H), 3.77-3.68 (m, 2H), 3.18-3.13 (m, 2H), 2.17-2.13 (m, 2H), 2.03-2.00 (m, 2H); ESI MS m/z 414 [M+H]+; HPLC (Method C)>99% (AUC), tR=12.9 min.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.N.C([BH3-])#N.[Na+].[BH4-].[Na+].[Li].[Na]>>[CH2:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)CCNC2
Agent: N
Agent: [BH3-]C#N
Agent: [BH4-]
Product: C1=CCC2CCNCC2=C1

Procedure:
heating a mixture of an amine compound of the formula 4 ##STR4## and pure acid compound, formula 5 R1 ? ? ##STR5## at 200° C. for about 2 hours under argon or other inert gas to obtain amide compound 6 of the following formula ##STR6## (b) contacting compound 6 with phosphorous oxychloride to produce the 1,2-dehydro derivative of compound 7 shown below: ##STR7## which need not be isolated; (c) neutralizing the 1,2-dehydro derivative of compound 7 with aqueous ammonia and reducing with sodium cyanoborohydride or sodium borohydride to give racemic 7 which is then resolved by optically active acids to the compound tetrahydroisoquinoline (+)-7 to (-)-7 ##STR8## (d) treating of (-)-7 with lithium or sodium in liquid ammonia as a reducing agent to give hexahydroisoquinoline, compound (-)-8 ##STR9## and formylating compound (-)-8 to give 10 ##STR10## and introducing a protective group for the nitrogen in the subsequent steps of the reaction where the reagent for formylation of 8 to 10 is phenylformate chloral or ethyl formate
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].F[C:26](F)(F)[CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15]([N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH3:26])[CH2:28]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: FC(F)(F)C1CCCNC1
Reactant: CC#CCOc1ncnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(N2CCCC(C)C2)c1F
Temperature: 70 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 0.2 g of 4-(2-butynyloxy)-5-fluoro-6-chloropyrimidine, 0.28 g of potassium carbonate and 0.15 g of 3-trifluoromethylpiperidine was added therein, and the mixture was stirred for 5 hours at 70° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 4-(2-butynyloxy)-5-fluoro-6-(3-methylpiperidino)pyrimidine (hereinafter, referred to as Compound (26)).