Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)N(C)CCC1.Cl[C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].C(O)C.C1COCC1>C(O)CCC>[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH:30][C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Clc1ncnc2[nH]c(-c3ccccn3)cc12
Reactant: Nc1cccc(Cl)c1
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4ccccn4)cc23)c1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
Under an argon atmosphere, 40 ml of DMPU are added to 6.53 g (28.3 mmol) of 4-chloro-6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidine and 4.46 ml (42.5 mmol) of 3-chloro-aniline in 90 ml of n-butanol and the reaction mixture is stirred at 140° C. for 12 hours. The dark-brown suspension is cooled and filtered. Further product can be obtained from the mother liquor by precipitation with 100 ml of water. Digestion with ethanol/THF yields the title compound; m.p.>300° C.; 1H-NMR (360 MHz, DMSO-d6): 12.49 and 9.66 (2s, 2H), 8.63 (d, J=5, 1H), 8.40 and 8.25 (2s, 2H), 7.91 (m, 2H), 7.84 (d, J=8, 1H), 7.57 (s, 1H), 7.33 (m, 2H), 7.06 (d, J=8, 1H); HPLC: tRet (Grad20)=10.1 min; MS: (M)+ =321.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:44][CH2:43]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:43][CH2:44]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CC1
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (300 mg, 0.74 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amine (8d) (329 mg, 1.48 mmol) in dimethylformamide (5 mL) were added N,N-diisopropylethylamine (0.4 mL, 2.22 mmol) and HATU (423 mg, 1.11 mmol). After stirring at room temperature for 1 h, water (50 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (284) (430 mg, 96.32%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][C:17]=3[CH2:26][NH:27][CH3:28])[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:18][C:17]=3[CH2:26][NH:27][CH3:28])[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Product: CNCc1cc(CCCOC(=O)C(C)(C)C)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-methyl-4-[4-(3-hydroxypropyl)methylaminomethylphenyl]cyclohexylamine and pivaloylchloride. Melting point 100°-102° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.Br[CH2:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:3]2[O:16][CH2:18][CH2:19][CH2:20][N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCOc2c(Br)cccc21
Temperature: 75 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl (3-bromo-2-hydroxyphenyl)carbamate (D52) (3 g, 10.41 mmol) in acetone (30 mL) was added 1,3-dibromopropane (3.17 mL, 31.2 mmol), K2CO3 (11.51 g, 83 mmol) and the mixture stirred at 75° C. for 16 hours. The reaction was then cooled to RT, filtered, the filtrate was evaporated. The residue was then purified on silica eluting with a gradient of 0-10% ethyl acetate in cyclohexane to afford the title compound (2.2 g). LCMS (A): m/z (M+H)+328/330, C14H18BrNO3 requires 327/329 (acidic).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][OH:5].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:5][CH2:4][CH:3]([NH:6][C:7]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:2]([F:17])([F:18])[F:1])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC(CO)C(F)(F)F)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(NC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate (300 g, 1.14 mol) in dichloromethane (2500 mL) were added triethylamine (128 g, 1.27 mol) and methanesulfonylchloride (144 g, 1.26 mol). After 2 hours, the reaction mixture was quenched with water (1000 mL) and extracted with dichloromethane (3×300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoropropyl methanesulfonate. The material was used without further purification.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](CCO)=[CH:26][CH:25]=1>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH2:7][C:27]1[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=1)=[O:4]
Reactant: OCCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Agent: [Ti+4]
Agent: CC[O-]
Product: CN1CCC2(C)c3cc(C(=O)C(=O)OCCc4ccc(Cl)cc4)ccc3N(C)C12

Procedure:
To a chilled (0° C.) solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (1.18 g) in 4-chlorophenylethyl alcohol (31 ml) was added titanium (IV) ethoxide (0.30 ml) under a nitrogen atmosphere with stirring. The mixture was gently heated without refluxing for 4 hours. The 4-chlorophenylethyl alcohol was removed by distillation under high vacuum and the crude residue was dissolved in dichloromethane (20 ml) and washed successively with two 100 ml portions of saturated ammonium chloride solution, two 100 ml portions of saturated sodium bicarbonate solution and 100 ml of brine. The organic phase was dried (Na2SO4) filtered, and purified using preparative HPLC (silica gel, 3% methanol in dichloromethane as the loading solvent and eluent). The appropriate fractions were combined and the solvent removed under vacuum. Concentration of the appropriate fractions yielded 0.87 g of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, 4 -chlorophenylethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1.ClCCl>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 100 °C

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (900 mg) in toluene (20 mL) at 40° C. was added phosphorus tribromide (0.10 mL) and the reaction mixture was heated at 100° C. for 16 h. After cooling to room temperature, the reaction was diluted with dichloromethane (40 mL) and washed with saturated aqueous sodiumhydrogen carbonate solution (2×40 mL). The organic layer was dried (MgSO4) and reduced in vacuo to give 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH:25]4[CH2:28][N:27]([S:29]([NH:32]C(=O)OC(C)(C)C)(=[O:31])=[O:30])[CH2:26]4)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>CC#N>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]2[N:24]=[C:23]([CH:25]3[CH2:28][N:27]([S:29](=[O:31])(=[O:30])[NH2:32])[CH2:26]3)[O:22][N:21]=2)=[CH:14][C:13]=1[NH:12][C:10]([C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1)=[O:11]
Reactant: Cc1ccc(-c2noc(C3CN(S(=O)(=O)NC(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(-c2noc(C3CN(S(N)(=O)=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-ylsulfonylcarbamate (128) (25 mg, 0.0452 mmol) in CH3CN (0.5 mL) was added HCl (4N in dioxane, 1 mL). The reaction was stirred for 30 minutes. The solvent was concentrated and the crude was purified by preparative HPLC to give N-(2-methyl-5-(5-(1-sulfamoylazetidin-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F23). 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.51-9.48 (m, 1H), 8.67 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.87-7.84 (m, 2H), 7.66-7.61 (m, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.29-7.25 (m, 1H), 7.13 (s, 2H), 4.24-4.18 (m, 1H), 4.16-4.12 (m, 2H), 4.05-4.01 (m, 2H), 2.37 (s, 3H). MS m/z 454.59 (M+1)+.
Reaction SMILES: C12(C3C=CC(OCC(N[C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23](O)=[O:24])=O)=CC=3)CC3CC(CC(C3)C1)C2.FC(F)(F)C1C=C([NH2:39])C=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([NH2:39])(=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:20][CH:21]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Yield: 248.3 %

Procedure:
To a solution of 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid (50.0 mg, 0.13 mmol), 3-trifluoromethyl-phenylamine (31.5 mg, 0.03 ml 0.20 mmol), EDC (37.4 mg, 0.20 mmol) and HOBt (30.0 mg, 0.20 mmol) in DMF 1.3 mL was added DIPEA (0.04 ml, 0.20 mmol). Reaction mixture was stirred, and separated by ethyl acetate and 10% HCl. It was sequentially washed with brine and water, and dried over MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel flash column chromatography (EtoAC:Hexane=1:3) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-3-trifluoromethyl-phenyl)-benzamide as a white solid (39.1 mg, 54.9% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([C:11]#[N:12])[CH:4]=1)#[N:2].CO.[H][H]>[OH-].[Na+].C1(C)C=CC=C(C)C=1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: N#Cc1cc(C#N)cc(C#N)c1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(C)c1
Solvent: CO
Product: NCc1cc(CN)cc(CN)c1
Yield: 79.1 %

Procedure:
In a 300 ml capacity, magnetic-stirring autoclave was sealed 15 g of 1,3,5-tricyanobenzene (MTN), together with 15 g of Raney nickel chromium catalyst (atomic ratio of Ni:Cr=49:1), 27 ml of methanol, 63 ml of m-xylene and 0.18 g of caustic soda. Hydrogen was charged under pressure into it at initial pressure of 100 kg/cm2G, and the reaction was carried out at 100° C., whereby 0.59 mole of hydrogen was absorbed for 35 minutes. The catalyst was filtered out, and the solvent was distilled off, followed by distilling under reduced pressure, thereby yielding 12.8 g of colorless crystals of 1,3,5-tris(aminomethyl)-benzene (MTA). The substance exhibited melting point of 49° to 51° C. and boiling point of 136° to 139° C./0.4 mmHg.
Reaction SMILES: Cl.[F:2][C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:13]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:6]2[CH2:5][CH2:4][C:3]([F:2])([C:9]3[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=4)[N:13]=3)[CH2:8][CH2:7]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3(F)CCNCC3)n2)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(F)(c3nc(COc4ccc(S(C)(=O)=O)cc4)cs3)CC2)nc1

Procedure:
A solution of 4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (4.0 g, 9.01 mmol), 2-chloro-5-ethyl-pyrimidine (1.55 g, 1.2 eq.) and DIPEA (4.7 g, 4 eq.) in 2-propanol (30 mL) in a sealed pressure vessel was stirred at 160° C. (oil bath temperature) overnight. After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 8.19 (2H, s), 7.87 (2H, d, J=9.2 Hz), 7.36 (1H, s), 7.10 (2H, d, J=9.2 Hz), 5.23 (2H, s), 4.69 (2H, m), 3.44 (2H, m), 3.03 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.15˜2.39 (4H, m), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C=O)C>[CH3:13][C:5]1[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=[C:3]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:4]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: C1CCNC1
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)nn2c(N)nnc12
Reaction time: 1.5 h

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 250 mg) was dissolved in DMF (2 ml) and admixed with pyrrolidine (2 ml). Thereafter, the reaction mixture was placed into the heating block at 80° C. with stirring for 1.5 h. Subsequently, the solvent was drawn off and the residue was admixed with a little water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. When the residue was dissolved in acetonitrile/water+0.05% TFA, a solid precipitated out, which was filtered off with suction and dried. 40 mg of 8-methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained. The mother liquor was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 11 mg of 8-methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained as the trifluoroacetic acid salt. 8-Methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1/[CH:12]=[CH:19]/[C:20]([OH:22])=[O:21]
Reactant: O=Cc1ccccc1Sc1ccc(Cl)cc1Cl
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccccc1Sc1ccc(Cl)cc1Cl
Temperature: 110 °C
Yield: 90.6 %

Procedure:
A mixture of the aldehyde (1.50 g, 5.3 mmol) from Example 1A, malonic acid (1.21 g, 11.6 mmol), piperidine (78.6 μL, 0.80 mmol) in 8.0 mL of anhydrous pyridine was heated at 110° C. for 2 hours. Gas evolution ceased during this period. Pyridine was then removed under vacuum. Water and 3N aq. HCl were then added with stirring. The desired cinnamic acid was then collected through filtration, washed with cold water and dried in a vacuum oven overnight to give 1.56 g (4.8 mmol, 91%) of white solid.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:14])[NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([Cl:13])[N:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:12][C:11]1[C:6]([NH:5][C@H:4]([CH3:14])[CH:3]=[O:2])=[N:7][C:8]([Cl:13])=[N:9][CH:10]=1
Reactant: COC(=O)[C@@H](C)Nc1nc(Cl)ncc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@H](C=O)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 40.0 g (135.8 mmol) of methyl-N-(5-bromo-2-chloropyrimidin-4-yl)-D-alaninate in 800 ml of toluene is mixed at −78° C. with 310 ml of a 1.2 molar solution of diisobutyl aluminum hydride. After 30 minutes, it is carefully quenched with methanol. The batch is heated to room temperature and diluted with 1000 ml of tert-butyl methyl ether. It is washed successively with 1N HCl (3×100 ml), saturated sodium bicarbonate solution (3×) and saturated NaCl solution (3×). The organic phase is dried (MgSO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 4:1-1:1). 22.5 g (83.9 mmol, corresponding to 62% of theory) of the product is obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([O:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:33])=[O:32]
Reactant: COC(=O)c1ccccc1CCCC(O)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1CCCC(Cc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 30d (2.27 g, 7.62 mmol) and Et3N (2.12 mL, 15.2 mmol), MsCl (1.2 mL, 15.2 mmol) was added dropwise at 0° C. After addition was complete, the reaction was stirred at rt until LC-MS analysis indicated the total consumption of the SM. The solvent was removed and the residue was purified by CC using PE:EA=5:1 as mobile phase to afford the desired product (2.9 g, quant.)
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:26]#[C:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH:19]3[CH2:23][O:22]C(C)(C)[O:20]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O>C(O)=O>[C:1]12([C:11]3[CH:12]=[C:13]([C:26]#[C:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH:19]([OH:20])[CH2:23][OH:22])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(C#Cc2ccc(OCC3COC(C)(C)O3)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: O
Solvent: O=CO
Product: COC(=O)c1ccc(C#Cc2ccc(OCC(O)CO)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 100 °C

Procedure:
450 mg (0.9 mmol) of methyl 4-[3-(1-adamantyl)-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl-ethynyl]benzoate were placed in suspension in 10 ml of a formic acid solution (40%) and heated at 100° C. for three days. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulphate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 220 mg (53%) of the expected methyl ester were collected, which ester had the melting point 202°-3° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@:6]12[CH2:14][NH:13][CH2:12][C@H:11]1[CH2:10][S:9][C:8]([NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:7]2.CN(C)C(N(C)C)=N.[F:32][C:33]1[CH:34]=[N:35][C:36](Cl)=[N:37][CH:38]=1.O>CS(C)=O>[F:32][C:33]1[CH:34]=[N:35][C:36]([N:13]2[CH2:12][C@@H:11]3[C@@:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)([N:7]=[C:8]([NH:15][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:9][CH2:10]3)[CH2:14]2)=[N:37][CH:38]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CNC[C@H]2CS1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC1=N[C@@]2(c3cccs3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 50 °C
Yield: 71 %

Procedure:
A solution of N-[(4aR,7aR)-7a-(2-thienyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (7.7 g, 22.4) and N,N,N′,N′-tetramethylguanidine (3.39 mL, 26.9 mmol) in dimethyl sulfoxide (61 mL) is treated with 5-fluoro-2-chloropyrimidine (2.25 mL, 23.54 mmol) and the resulting solution is heated at 50° C. for 4 hours. The solution is cooled to room temperature and added to water (500 mL). The crude product is purified over silica gel using a 5 to 50% gradient of ethyl acetate/hexanes to give the title compound (7 g, 71%). ES/MS (m/e): 440 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C@@H:14]([CH2:17][OH:18])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C@@H:14]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of crude ((S)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol (1.65 g, 6.06 mmol) in dry DCM (10 ml), was added triethylamine (0.88 ml). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.49 ml) was added slowly dropwise to reaction mixture. The mixture was stirred at RT for 1 h and then 10 ml of aq 1 M HCl was added. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried with Na2SO4 The solvents were removed under reduced pressure and the crude product (2.22 g) was crystallized from IPA (15 ml), which gave a white solid (1.50 g).