Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)=O.C(S[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1)C1C=CC=CC=1.[Cl:22]N1C(C)(C)C(=O)N(Cl)C1=O.[S:33](S([O-])=O)([O-:36])(=O)=[O:34].[Na+].[Na+]>C(Cl)Cl.O>[N+:19]([C:18]1[C:13]([S:33]([Cl:22])(=[O:36])=[O:34])=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: O=[N+]([O-])c1cccnc1SCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
AcOH (6 ml) and water (12 ml) were added to a solution of 2-benzylsulfanyl-3-nitro-pyridine 437 (3.0 g, 12.2 mmol) in DCM (42 ml) and the mixture was cooled to 0° C. A suspension of 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (7.20 g, 36.58 mmol) in DCM (24 ml) was added portionwise to the vigorously stirring solution. The mixture was allowed to slowly warm to 25° C. and stirring was continued for 16 h. The mixture was poured into 5% aq. sodium metabisulfite solution (50 ml) and the aqueous phase was extracted with DCM (100 ml). The organic phase was washed with water, sat. NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (2.7 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([F:10])=[C:4](F)[C:5]([F:8])([F:7])[F:6].[CH2:13](O)[CH:14]=[CH2:15].[OH-:17].[K+]>O>[CH2:15]([C:3]([F:10])([C:2]([F:1])([F:11])[F:12])[C:4](=[O:17])[C:5]([F:6])([F:7])[F:8])[CH:14]=[CH2:13]
Reactant: FC(=C(F)C(F)(F)F)C(F)(F)F
Reactant: [OH-]
Reactant: C=CCO
Agent: [K+]
Solvent: O
Product: C=CCC(F)(C(=O)C(F)(F)F)C(F)(F)F
Reaction time: 8 h

Procedure:
396 g (1.98 mol) of octafluorobut-2-ene is condensed into 116 g (2 mol) of allyl alcohol at -5° C. Then 113 g (1.98 mol) of KOH, dissolved in 150 ml of water, is slowly added dropwise over the course of 3 hours, the temperature being maintained at 0°-5° C. Stirring continues overnight at room temperature and working-up is performed in the same way as in Example 2a.
Reaction SMILES: Br[C:2]1[C:3]([F:30])=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([CH2:18][F:19])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9]3)[CH:7]=1.C(OC[C@@H]1OC[C:43]2(C3C=C(C#N)C(F)=CC=3F)[N:44]=C(NC(=O)C3C=CC=CC=3)SCC2C1)C1C=CC=CC=1>>[C:43]([C:2]1[C:3]([F:30])=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([CH2:18][F:19])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:9]3)[CH:7]=1)#[N:44]
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Reactant: N#Cc1cc(C23CO[C@@H](COCc4ccccc4)CC2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Product: N#Cc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C13) was converted to the product using the method described for the synthesis of N-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C10) in Example 1. Yield: 98.5 mg, 0.220 mmol, 44%. LCMS m/z 446.2 [M+H+]. 1H NMR (400 MHz, CD3OD), δ 8.06 (d, J=7.2 Hz, 2H), 7.85 (t, J=7.8 Hz, 1H), 7.54-7.57 (m, 1H), 7.45-7.49 (m, 2H), 7.37 (dd, J=12.1, 9.2 Hz, 1H), 4.44-4.51 (m, 1H), 4.32-4.39 (m, 1H), 4.06-4.10 (m, 1H), 3.89-4.0 (m, 2H), 3.11-3.19 (m, 1H), 2.96 (dd, J=13.3, 4.1 Hz, 1H), 2.75 (dd, J=13.3, 2.9 Hz, 1H), 1.83-1.93 (m, 1H), 1.64-1.69 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[CH3:20][O-:21].[Na+]>C1COCC1>[OH:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[N:3]2[C:2]([O:21][CH3:20])=[N:6][N:5]([CH3:7])[C:4]2=[O:8])=[CH:14][CH:15]=1
Reactant: C[O-]
Reactant: Cn1nc(Cl)n(-c2cccc3ccc(O)cc23)c1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nn(C)c(=O)n1-c1cccc2ccc(O)cc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the tide compound of Step F (3.3 g) in THF (38 mL) was added a solution of sodium methoxide (6.5 mL, 30% in methanol) while stiring under N2. The mixture was heated at 50° C. for 6 h and cooled to room temperature and left to stir overnight. The reaction was quenched with water and extracted three times with methylene chloride and then three times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Trituration (ethyl acetate:hexane 1:1) of the crude product provided 1.61 g of the title compound of Step G as a light brown solid melting at greater than 250° C. 1H NMR (Me2SO-d6): δ 10.00 (s,1H), 7.93 (m,2H), 7.47 (dd,1H), 7.36 (t,1H), 7.15 (dd,1H), 6.73 (d,1H), 3.86 (s,3H), 3.39 (s,3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>[C:15]1([CH:14]=[CH:13][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(Br)ccnc2c1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: Clc1ccc2c(C=Cc3ccccc3)ccnc2c1
Temperature: 120 °C
Yield: 50.8 %

Procedure:
A mixture of 4-bromo-7-chloroquinoline (24.3 g, 0.1 mol), styrene (12.0 g, 0.125 mol), tri(o-tolyl) phosphine (0.4 g, 1.3 mmol), palladium acetate (0.2 g, 0.89 mol) and triethylamine (120 mls) was charged into a 300 ml stirred pressure vessel and heated at 120° C. for 17 hours. The mixture was cooled, filtered to remove triethylamine hydrobromide, and the solids washed with ethyl acetate (250 ml). Solvents were evaporated under reduced pressure and the residue dissolved in ethyl acetate (500 ml). The solution was washed with water and brine, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallisation of the residue from ethyl acetate: hexane gave the product (13.5 g, 51%) as an orange solid, mp 120-122° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18]1[CH2:22][NH:21][C:20](=[O:23])[CH:19]=1.[H-].[Na+].O>CS(C)=O.C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:21]3[CH2:22][C:18]([O:17][CH3:16])=[CH:19][C:20]3=[O:23])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: COC1=CC(=O)NC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.1 %

Procedure:
A solution of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran (15 g) and 4-methoxy-3-pyrrolin-2-one (8.5 g) in dimethylsulfoxide (40 ml) was stirred and sodium hydride (80% dispersion in oil, 2.2 g) was added. The mixture was stirred at room temperature for 5 hours. Water (50 ml) was slowly added, and the resulting solution extracted with ethyl acetate (2×50 ml). After drying the organic layer with sodium sulfate the solvent was removed under reduced pressure and the residual oil chromatographed on silica gel (4% methanol in methylene chloride). The product obtained was dissolved in diethylether and precipitated with pentane to afford 4 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-methoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 256° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH2:9][C:10](=[O:21])[CH2:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)=O)[CH:3]=1.[NH3:23]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:23][C:12]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=3)=[CH:11][C:10](=[O:21])[CH:9]=2)[CH:3]=1
Reactant: O=C(CC(=O)c1cc(Cl)ccn1)CC(=O)c1cc(Cl)ccn1
Reactant: N
Solvent: CC(C)O
Product: O=c1cc(-c2cc(Cl)ccn2)[nH]c(-c2cc(Cl)ccn2)c1
Temperature: 4 °C

Procedure:
38.5 g (0.114 mol) of 1,5-bis(4-chloropyridin-2-yl)pentane-1,3,5-trione are suspended in 1.25 l of 2-propanol. A total of 230 ml of 25% (w/w) ammonia solution is added at 60° C.-70° C. over the course of five and a half hours. The mixture is cooled to 4° C. and the whitish 4,4″-dichloro-1′H-[2,2′;6′,2″]terpyridin-4′-one formed is filtered off. 1H-NMR (360 MHz, DMSO-d6): 8.65 (d, 2H, J=5.4 Hz); 8.57 (d, 2H, J=2.2 Hz); 7.82 (s, 2H); 7.59 (dd, 2H, J=5.4,2.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18](=[O:19])[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[BH4-].[Na+]>C(O)C.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([OH:19])[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1nc2c(n1CCO)C=Cc1cc(Cl)ccc1C2O

Procedure:
A mixture of the product of step (i) (0.79 g) in ethanol (100 ml) was treated with sodium borohydride (0.207 g) followed by heating at reflux for 4 hours. The mixture was treated with a few drops of acetone and then concentrated under reduced pressure to dryness. Used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1CN(Cc2ccccc2)CCC1c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.3 %

Procedure:
58 ml (203 mmol) of sodium dihydrido-bis-(2-methoxyethoxy)aluminate (70% in toluene) were added dropwise under argon at room temperature while stirring to a solution of 17.4 g (58.5 mmol) of (RS)-[1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridin-3-yl]-methanol in 580 ml of absolute toluene. Subsequently, the mixture was stirred at 80° C. for 4 hours. 100 ml of water were added dropwise to the reaction mixture at room temperature, with working-up thereafter being carried out by extraction with water and ethyl acetate. The crude product was chromatographed on silica gel with hexane and ethyl acetate as the eluent. There were obtained 3.90 g (44% of theory) of (3RS,4SR)-[1-benzyl-4-(4-fluoro-phenyl)-piperidin-3-yl]-methanol; MS: 300 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])O.[Na+].[C:25]12([NH2:35])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.[H][H]>C(O)C.[C].[Pd].O1CCCC1.O>[C:25]12([NH:35][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]5[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=5[N:12]=4)=[CH:4][C:3]=3[NH2:17])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.1 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (195 mg, 2.32 mmol) and 1-adamantylamine (185 mg, 1.22 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered off, washed with water and then dried. The crystals obtained were added to a tetrahydrofuran (5 mL) solution containing 10% palladium-carbon (100 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 6 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (67.0 mg, 16% yield) as brown crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[NH:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:9]3=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Cl[CH2:23][C:24]#[N:25]>CS(C)=O.O>[C:24]([CH2:23][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[NH:17][C:8]=13)[N:1]=[CH:2][CH:3]=[N:4]2)#[N:25]
Reactant: c1ccc2c(c1)[nH]c1ccc3nccnc3c12
Reactant: [H][H]
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc2nccnc2c2c1[nH]c1ccccc12
Temperature: 35 °C
Yield: 69 %

Procedure:
Indoloquinoxaline (10.95 g) is dissolved in dry dimethyl sulfoxide (150 ml) under nitrogens and sodium hydride (1.3 g) is added with good stirring at 35° C. After completion of hydrogen gas generation (about 30 minutes), chloroacetonitrile (4.0 g) is dropped in with stirring at 20° C. After 1 day at this temperature water (20 ml) is added and crystals formed of pure 6-cyanomethylindoloquinoxaline (8.9 g) are sucked and washed with methanol followed by water. The mother liquor is poured into a large amount of water and the formed precipitate is dried and purified by chromatography on silica gel with methylene chloride/methanol as eluent. In this manner further 3.0 g of 6-cyanomethyl-6H-indolo(2,3-b)quinoxaline are obtained. The total yield thus is 11.9 g, 92%, mp. 231°-232° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.[CH3:12][CH2:13][C:14](Cl)=[O:15].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>ClCCl.O.[OH-].[Na+]>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[C:19]=1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[C:14](=[O:15])[CH:13]([CH3:12])[N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: Cc1cccc(C)c1NCCCCCCc1cccnc1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1N(CCCCCCc1cccnc1)C(=O)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A solution of 1.7 g of 2,3-dihydro-1,3-dioxo-1H-isoindole-alpha-methyl-acetyl chloride in 20 ml of dry dichloromethane was added dropwise to a solution of 2.0 g N-(2,6-dimethylphenyl)-3-pyridinehexanamine in 20 ml of dichloromethane. The reaction mixture was stirred overnight at room temperature, diluted with water and aqueous sodium hydroxide and the layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water, dried with potassium carbonate and concentrated. The residue was crystallized from ethyl acetate-hexane to give 2.3 g of rac.-2,3-dihydro-N-(2,6-dimethylphenyl)-alpha-methyl-1,3-dioxo-N-[6-(3-pyridinyl)hexyl]-1H-isoindole-2-acetamide, mp 113°-115° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5](Cl)(Cl)=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1>CCOCC.O1CCCC1>[CH3:23][CH:17]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:5]([O:4][CH2:1][C:2]#[CH:3])=[O:6])=[CH:11][CH:12]=2)=[N:21][NH:20][C:19](=[O:22])[CH2:18]1
Reactant: O=C(Cl)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: C#CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCOC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
2.8 g (49.9 millimoles) of prop-2-ynol are added dropwise to a stirred solution of 9.9 g (100 millimoles) of phosgene in 100 ml of absolute ether at -10° C. and the reaction solution is then stirred for 1 hour at the same temperature. Thereafter it is stirred for one hour at room temperature and the excess phosgene is then removed by means of a dry stream of nitrogen, after which the ether is removed under reduced pressure at room temperature. The prop-2-ynyl chloroformate which remains (5.2 g) is added, at room temperature, to a solution, prepared by the method described in Example 31, of 5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 150 ml of absolute tetrahydrofuran. The reaction mixture is then refluxed for 1 hour and concentrated to about 70 ml. Water is added and the product is filtered off and recrystallized first from ethanol/water, then from acetone/water and finally from ethanol, giving 2.9 g (41% of theory) of 4,5-dihydro-5-methyl-6-[p-(prop-2-ynyloxycarbonylamino)-phenyl]-3(2H)-pyridazinone as colorless crystals, of melting point 204°-205° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[CH:32]=3)[C:27]([CH3:43])([CH3:42])[CH2:26]2)=[O:24])[CH2:10][C@H:9]1[CH3:44])=O)(C)(C)C.[ClH:45]>CCOC(C)=O.O1CCOCC1>[ClH:45].[ClH:45].[F:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][C:31]1[CH:32]=[C:33]2[N:25]([C:23](=[O:24])[CH2:22][N:11]3[CH2:10][C@@H:9]([CH3:44])[NH:8][CH2:13][C@@H:12]3[CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[CH3:21])[CH2:26][C:27]([CH3:42])([CH3:43])[C:28]2=[N:29][CH:30]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccccc3F)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccccc4F)cc32)[C@@H](CN2CCOC[C@H]2C)CN1

Procedure:
(2R,5S)-4-{2-[6-(2-Fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.43 g, 2.35 mmol) was dissolved in EtOAc (34 mL) and 4 M HCl in dioxane (59 mL) and stirred at room temperature for 18 h. The solvent was removed in vacuo, then residue was re-dissolved in methanol and concentrated. The crude product was purified by recrystallisation (isopropanol/diethyl ether) to give the title compound (0.90 g). 1H NMR (DMSO-d6): 10.64-10.27 (1H, m), 9.97-9.64 (1H, m), 9.43-9.02 (1H, m), 8.23 (1H, s), 8.08 (1H, s), 7.43-7.35 (1H, m), 7.35-7.26 (1H, m), 7.22-7.13 (2H, m), 4.07-3.84 (8H, m), 3.69-3.30 (6H, m), 3.26-2.95 (4H, m), 2.91-2.82 (1H, m), 1.32 (6H, d), 1.28-1.13 (6H, m). MS: [M+H]+=510.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17](Br)[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:34]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:40]2)=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:38]3[CH:39]=[CH:40][C:41]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:42]=4)[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cc(Br)c3c(N)ncnn23)c1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Temperature: 150 °C

Procedure:
To a solution of [3-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-carbamic acid tert-butyl ester (2.65 g, 6.1 mmol) in DMF (20 mL), 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (3.26 g, 9.8 mmol), Pd(PPh3)4 (700 mg, 0.6 mmol) and 2 N Na2CO3 (12 mL) were added. The mixture was degassed for 20 min and was then heated to 150° C. in microwave reactor for 10 min. After cooling, the mixture was partitioned between EtoAc/H2O and the organic layer was separated and dried. Biotage® chromatography (50-100% EtOAc) provided the title product as off white solid 2.6 g (76%). NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.10 (d, 2 H), 0.9 (s, 9 H); ES-MS m/z 561.34 [M+H]+, HPLC RT (min) 4.06.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH3:11])[CH:9]=[C:8](I)[C:6]=2[N:7]=1.[CH3:13][S:14]([NH:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH3:11])[CH:9]=[C:8]([C:22]3[CH:23]=[C:18]([NH:17][S:14]([CH3:13])(=[O:15])=[O:16])[CH:19]=[CH:20][CH:21]=3)[C:6]=2[N:7]=1
Reactant: Cn1cc(I)c2nc(Cl)ncc21
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)c2nc(Cl)ncc21
Temperature: 100 °C
Yield: 68 %

Procedure:
To a solution of 2-chloro-7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (0.140 g, 0.48 mmol, 1.0 eq.) in DMF (6 ml) was added 3-methanesulfonylaminophenylboronic acid (0.124 g, 0.576 mmol, 1.2 eq.) followed by aqueous Na2CO3 (2M, 0.7 ml, 1.44 mmol, 3.0 eq.). A flow of nitrogen was bubbled through the mixture during 15 to 20 min before adding Pd[PPh3]4 (0.055 g, 0.048 mmol, 0.1 eq.). The mixture was then heated up to 100° C. overnight. After cooling down the reaction mixture to room temperature a large amount of water (around 60 ml) was added and the mixture extracted with ethyl acetate (3 times). After evaporation the residue was purified by column chromatography using petroleum spirit/ethyl acetate (1:4) as eluent. The product was obtained as a pale yellow solid (110 mg, 68%). LRMS (EI): m/z calcd for [M+H]+ 337.05 found 337.2.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:13]([CH2:14][CH2:15][CH2:16][C:17](O)=[S:18])=[N:12][N:11]=[N:10]1.[CH2:20]1[CH2:30][CH2:29][N:28]2[C:23](=NC[CH2:26][CH2:27]2)[CH2:22][CH2:21]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:27]([N:28]([CH:23]1[CH2:22][CH2:21][CH2:20][CH2:30][CH2:29]1)[C:17](=[S:18])[CH2:16][CH2:15][CH2:14][C:13]1[N:9]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[O:2][CH3:1])[N:10]=[N:11][N:12]=1)[CH3:26]
Reactant: COC1CCCCC1n1nnnc1CCCC(O)=S
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1C1CCCCC1OC)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-[1-(2-Methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl]thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, and the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After distilling off chloroform, the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-4-[1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl]thiobutyramide (yield: 45%).