Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](I)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20](=[CH2:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>ClCCl.O>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]/[C:20](=[CH:28]\[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])/[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)I)cc1
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC/C(=C\S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.4 %

Procedure:
To a solution of 4-nitrobenzenesulphonyl iodide (1.49 g, 4.65 mmol) in dichloromethane (6 mL) at room temperature was added tert-butyl 2-(2-methoxyethoxymethyl)acrylate (0.68 g, 3.1 mmol). The mixture was stirred at room temperature for 3.5 hours and triethylamine (0.88 mL, 6.2 mmol) added dropwise. The reaction was stirred for 16 hours, diluted with distilled water (25 mL) and dichloromethane (10 mL) and the layers separated. The aqueous layer was further extracted with dichloromethane (5 mL) and the combined organic extracts were washed with 1.0N aqueous hydrochloric acid solution (20 mL), 5% aqueous sodium thiosulphate solution (20 mL) and distilled water (20 mL). The dichloromethane phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a brown oil (1.20 g). The crude product was purified by chromatography on silica by gradient elution with hexane/ethyl acetate mixtures to give, after combination and evaporation of appropriate fractions, the title compound as a yellow oil (0.78 g, 61.9%), Rf =0.33 (silica; hexane/ethyl acetate, 2:1), (MH+ 402.88, 1.07%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[C:13](=S)=[S:14].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[SH:14][C:13]1[O:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[N:9][N:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2nnc(S)o2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(hydroxymethyl)benzoic hydrazide CAS [58855-42-8] (1.4 g, 8.4 mmol) in ethanol (14 mL) were added carbon disulfide (1.12 mL, 18.5 mmol) and triethyl amine (1.3 mL, 9.3 mmol). After heating to reflux for 16 h with stirring, the reaction mixture was cooled to RT and diluted with ethyl acetate. The mixture was washed with 10% HCl solution and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (65% ethyl acetate in hexanes) gave 1.62 g of [4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl]methanol as a colorless solid. 1H NMR (600 MHz, CD3OD) δ 7.90 (ddd, J=0.59, 2.05, 8.51 Hz, 2H), 7.54 (d, J=7.92 Hz, 2H), 4.68 (s, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=[CH:33][C:34]=1[CH2:35]Br>>[Br:28][C:29]1[CH:30]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]#[N:44])[CH:32]=[CH:33][C:34]=1[CH2:35][N:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][CH2:20][C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:27])[CH3:26])[C:15]1=[O:25]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2Br)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R) -yl]-butanamide (Example 57, Step A) and 3'-bromo-4'-bromomethyl-1,1'-biphenyl-2-nitrile by the procedure described in Example 69, Step D. 1H NMR (200 MHz, CDCl3): 1.33 (s,3H), 1.34 (s,3H), 1.40 (s,9H), 1.91 (m,1H), 2.43 (d,14Hz,1H), 2.55 (d,14Hz,1H), 2.55-2.90 (m,3H), 4.62 (m,1H), 4.95 (d,16Hz,1H), 5.28 (s,1H), 5.34 (d,16Hz,1H), 6.63 (d,7Hz,1H), 7.10-7.25 (m,4H), 7.45 (m,4H), 7.64 (m,1H), 7.75 (m,2H). FAB-MS (Li spike): calculated for C34H37BrN4O4 644, 646; found 651 (13%); 653 (15%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(CCCCCCc3nnn[nH]3)oc2-c2ccccc2)cc1
Yield: 35.4 %

Procedure:
The procedure is as in the preceding example, heating 1 g of 7-(4,5-diphenyl-2-oxazolyl)heptanenitrile, twice 0.9 g of sodium azide and twice 0.7 g of ammonium chloride in 20 cm3 of dimethylformamide. The solid residue derived from the extractions is crystallised in a mixture of ethyl acetate (5 cm3) and diisopropyl ether (15 cm3). 0.4 g (35%) of 5-[6-(4,5-diphenyl-2-oxazolyl)hexyl]tetrazole is obtained in the form of white crystals, melting point 132° C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([CH2:33]Br)=[CH:31][CH:32]=1)=[O:27]>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:33][C:30]4[O:29][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:32][CH:31]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)o1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Product: COC(=O)c1ccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of example 1 step (iii) (1.1 g) and 5-bromomethyl-2-furancarboxylic acid methyl ester (0.96 g)(J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807) according to the method of example 1 step (iv). Purification was by chromatography eluting with 50-80% ethyl acetate in isohexane. Yield 1.24 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([Cl:10])=C([CH:9]=1)C#N.[OH-:13].[Na+].[CH3:15][CH2:16][OH:17]>O>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([Cl:10])=[C:15]([CH:9]=1)[C:16]([OH:13])=[O:17]
Reactant: [OH-]
Reactant: CCO
Reactant: COc1cc(Cl)c(C#N)cc1Br
Agent: [Na+]
Solvent: O
Product: COc1cc(Cl)c(C(=O)O)cc1Br
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxybenzonitrile (30.7 g, 124 mmol) and NaOH (127 g, 3.11 mol) in EtOH (500 mL) and water (250 mL) was refluxed overnight. After cooling to room temperature, EtOH was removed under reduced pressure. The mixture was diluted with water and neutralized with hydrochloric acid (3.0 N). The resulting solid was filtered and dried in vacuo to give title compound (32.9 g, quantitative) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13]O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: OCc1nc(-c2ccc(Cl)cc2)cs1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2csc(CBr)n2)cc1
Temperature: 120 °C
Yield: 16.6 %

Procedure:
To the solution of [4-(4-Chloro-phenyl)-thiazol-2-yl]-methanol (0.80 g, 3.55 mmol) in 10 ml of toluene was added PBr3 (0.51 ml, 5.33 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.17 g, 17%). The corresponding cyano derivative was also prepared by the same general method.
Reaction SMILES: [OH:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[H-].[Na+].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].O>C1COCC1>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([O:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC1(Cc2cncnc2)C=CC=CC1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)OC1(Cc2cncnc2)C=CC=CC1C(F)(F)F
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 0.5 g of 5-(1-hydroxy-2'-trifluoromethylbenzyl)-pyrimidine (produced according to Example 7) in 15 ml THF at room temperature, 0.2 g of NaH (80%) were added. Gas evolution was observed. After 30 minutes, 0.4 g of trimethylacetyl chloride were added to the reaction mixture and gas evolution was again observed. After 3 hours of stirring, the reaction mixture was worked up with water and the organic materials extracted with diethyl ether. The organic layer was dried (MgSO4), filtered and concentrated to a yellow oil. Elution on a silica gel column with a 1:1 mixture of diethyl ether and hexane yielded 0.56 g of 5-(1-trimethylacetoxy-2'-trifluoromethylbenzyl)-pyrimidine.
Reaction SMILES: C[CH:2]([CH:6]([OH:9])[CH2:7][Cl:8])[CH2:3][CH2:4][OH:5].Cl[C:11]1[CH:12]=[C:13]([CH2:19][OH:20])[C:14]([CH2:17][OH:18])=[CH:15][CH:16]=1>>[Cl:8][CH2:7][CH:6]([OH:9])[CH2:2][CH2:3][CH2:4][OH:5].[C:13]1([CH2:19][OH:20])[C:14]([CH2:17][OH:18])=[CH:15][CH:16]=[CH:11][CH:12]=1
Reactant: OCc1ccc(Cl)cc1CO
Reactant: CC(CCO)C(O)CCl
Product: OCCCC(O)CCl
Product: OCc1ccccc1CO

Procedure:
Example 8 was repeated except for using 20.9 g (137 mmoles) of 3-methyl-5-chloro-1,4-pentanediol and 4.94 g (28.6 mmoles) of 4-chloro-o-xylylene glycol, instead of 19.0 g (137 mmoles) of 5-chloro-1,4-pentanediol and 3.95 g (28.6 mmoles) of o-xylylene glycol, respectively, to obtain spiro[7-chloro-1,5-dihydro-2,4-benzodioxepin-4'-methylene-5'-methyl-3,2'-[1,3]dioxepane].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=1)[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>ClCCl>[Br:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:4]2[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[C:19]([CH3:18])[CH:20]=[N:21][CH:22]=3)[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](Nc1cccc(Br)n1)c1cccc(N)c1
Reactant: Cc1cncc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cncc(C(=O)Nc2cccc([C@H](C)Nc3cccc(Br)n3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.8 %

Procedure:
A mixture of N-[(1S)-1-(3-aminophenyl)ethyl]-6-bromopyridin-2-amine (70 mg, 0.24 mmol), 5-methylnicotinic acid (39 mg, 0.29 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol), 4-pyrrolidinopyridine (7 mg, 0.05 mmol) and triethylamine (0.08 mL, 0.58 mmol) in dichloromethane (3 mL) was stirred at room temperature for 17 hours. After this time the mixture was diluted with dichloromethane (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×15 mL) and brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-(3-{(1S)-1-[(6-bromopyridin-2-yl)amino]ethyl}phenyl)-5-methylnicotinamide (62 mg, 63%) as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:14]=[C:13](I)[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[N:26]=1.O>O1CCCC1.C(#N)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:14]=[C:13]([C:31]2[CH:32]=[C:33]3[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])=[N:26][N:27]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:50])[CH3:49])[C:28]3=[N:29][CH:30]=2)[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)N(C)C)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)N(C)C)cc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)c1
Yield: 69 %

Procedure:
In a personal chemistry microwave vial 5-Iodo-N,N-dimethyl-isophthalamic acid methyl ester (0.75 g, 2.25 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.08 g, 2.25 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium carbonate (20 ml) was degassed with nitrogen and 1,1′-bis(diphenylphosphino) ferrocenepalladium(II)-dichloride dichloromethane adduct (0.184 g, 0.23 mmol) was added and the vial sealed. This reaction mixture was irradiated in a microwave vial to 100° C. for 30 minutes. 100 ml water was added and this mixture was extracted with ethyl acetate (3×) the combined organic layers were dried over Magnesium Sulfate and purified by silica gel chromatography to yield 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-isophthalamic acid methyl ester as a white solid (0.87 g, 69% yield). MS: m/z 583.7 (M+H+).
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:20])=[N:9][N:10]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:6][CH:5]=1.O1CCOCC1.CNCCNC>[Cu]I.CN(C=O)C>[I:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:20])=[N:9][N:10]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A pressure tube containing copper (1) iodide (37.57 mg, 0.20 mmol), sodium iodide (591.42 mg, 3.95 mmol) and 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (600 mg, 1.97 mmol) was flushed with nitrogen before the addition of 1,4-dioxane, DMF (3 ml each) and N,N′-dimethylethane-1,2-diamine (0.021 ml, 0.20 mmol). The vessel was sealed and stirred at 115° C. overnight. Reaction was cooled and added to ice water (15 ml) before extracting into DCM (2×20 mL). Combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Crude material purified by column chromatography (Elution with 2% MeOH-DCM to 12% MeOH-DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 7.02 (3H, dd, J=5.5, 3.1 Hz), 7.73-7.53 (2H, m), 8.25 (1H, d, J=5.5 Hz), 9.25 (1H, s); LC-MS: m/z=+351.90 (M+H)+. This compound of 79% purity LC-MS was used for the next step without further purification
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6]([S:24][CH3:25])[C:3]=1[C:4]#[N:5].CCO.CCN(C(C)C)C(C)C.[NH2:38][NH2:39]>O>[CH3:23][NH:22][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:38][NH:39]3)=[C:6]([S:24][CH3:25])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:21])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCC[C@H]2C)n1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNc1nc(-c2cc(SC)c3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Into a sealable tube, 2-fluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}-6-(methylthio)benzonitrile (86 mg, 0.241 mmol), EtOH (5 mL), Hunig's base (0.042 mL, 1.44 mmol), and hydrazine anhydrous (0.045 mL, 0.241 mmol) were added, and the yellow suspension mixture was heated overnight at 100° C. in an oil bath. After overnight, there was yellow solution as well as a little amount of white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was further purified by flash column chromatography. The fractions containing product were combined, and the solvent was removed under reduced pressure to afford the title compound (20.5 mg) as a white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J=6.1 Hz, 3H), 1.67 (m, 1H), 1.84-2.10 (m, 3H), 2.61 (s, 3H), 2.79-2.91 (m, 3H), 3.41-3.66 (m, 2H), 4.27 (m, 1H), 5.09 (s, 2H), 6.23 (s, 1H), 6.44 (s, 1H), 7.34-7.46 (m, 1H), 7.72 (s, 1H), 11.75 (s, 1H).
Reaction SMILES: [CH2:1]([C@H:8]([NH2:23])[CH2:9][N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([C@H:8]([NH:23][C:37]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:38])[CH2:9][N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccsc1C1=CCN(C[C@@H](N)Cc2ccccc2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccsc1C1=CCN(C[C@H](Cc2ccccc2)NC(=O)C2CCCCC2)CC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A magnetically stirred solution of 0.5 g (1.52 mmol) of (1S)-1-Benzyl-2-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethylamine and 0.42 ml (3.04 mmol) of triethylamine in 30 ml of dry dichloromethane was cooled in an ice bath under a dry nitrogen atmosphere. A solution of 0.25 g (1.67 mmol) of cyclohexane carbonyl chloride in 6 ml of dry dichloromethane was added dropwise over 10 minutes. The resulting solution was stirred at 4° C. for 1 hour and then the ice bath was removed and stirring was continued overnight (app. 18 hours), during which time the reaction came up to room temperature. TLC on silica gel (4% methanol/dichloromethane) revealed the absence of starting material and a new product (Rf=0.5). The reaction was concentrated on a rotary evaporator and partitioned between 75 ml of ethyl acetate and 50 ml of 1N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The resulting oil was purified by flash chromatography on silica gel (4% methanol/dichloromethane) to give 0.34 g of the desired (S)-cyclohexanecarboxylic acid {1-benzyl-2-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-amide as oil which hardened upon exposure to vacuum. The compound was converted to its monofumerate·1.25 hydrate salt, yield=0.35 g (41%); mp=194-196° C.; [a]D25 =+5.86 (EtOH, c=0.5).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)([O-])=O.CO.[H][H]>C1(C)C=CC=CC=1.[Pd]>[N:35]1[CH:36]=[CH:37][C:32]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[N:9]([C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:33][CH:34]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 105.8 %

Procedure:
To a 500 ml round bottom flask equipped with a magnetic stir bar was added 5-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazole (1332 g, 27.6 mmol) and dissolved in a mixture of toluene:MeOH (120 ml: 40 ml). While stirring, Pd/C (1.5 g, 10% wet) was added. The mixture was then subjected to a hydrogen balloon and stirred overnight. Upon completion of the reaction, which was determined by LC/MS, the mixture was filtered through celite and concentrated under vacuum to give 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (13.21 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:28]3[CH2:31][CH2:30][CH2:29]3)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: C1CNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCC1)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), azetidine (0.1 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 1), 244 (3), 71 (5), 70 (bp), 69 (4).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.C[N:17](C)C=O.C(Cl)(=O)C(Cl)=O.N[C:28]1[CH:49]=[CH:48][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:30][CH:29]=1>CN(C)C(=O)C.O1CCCC1>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:30]=[C:29]([NH:17][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])[CH:28]=[CH:49][CH:48]=4)=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:47][CH2:46]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)nn1-c1ccccc1
Yield: 164.7 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (294 mg, 1.45 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (127 μL, 1.45 mmol), N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.97 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 255, the title compound (317 mg, 66%) was obtained as a white powder.
Reaction SMILES: [CH3:1][NH2:2].CO.[Cl:5][C:6]1[CH:11]=[C:10](I)[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1>CCCCCC>[Cl:5][C:6]1[CH:11]=[C:10]([NH:2][CH3:1])[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: CN
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Solvent: CCCCCC
Solvent: CO
Product: CNc1cc(Cl)ncc1C(F)(F)F
Temperature: 130 °C
Yield: 31 %

Procedure:
2 M Methylamine in MeOH (11.6 mL, 23.2 mmol) was added to 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (357 mg, 1.16 mmol) and the mixture was heated in a microwave reactor at 130° C. for 1 hour. The mixture was concentrated in vacuo. Preparative thin-layer chromatography, eluting with 20% EtOAc:hexane, gave 2-chloro-N-methyl-5-(trifluoromethyl)pyridin-4-amine (77 mg, 0.363 mmol, 31% yield).