Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:30][OH:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:34])C.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:30][OH:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:34])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C#N)n4)c3CO)ncc2c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C(N)=O)n4)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 10 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-3-carbonitrile (16 mg, 38.3 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1 mg, 2.33 μmol, Eq: 0.0608) were combined with ethanol (821 μl) and water (410 μl) to give a colorless solution. The reaction mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was diluted with DCM. The reaction mixture was filtered through glass fiber paper. The crude material was purified by preparative HPLC to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-3-carboxylic acid amide (11 mg, 66%, [M+H]+ 436) of lyophilized white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O1CCOCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[S:3][C:2]3[N:1]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:26][C:7](=[O:9])[C:6]=3[CH:5]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)sc1N
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(-c2ccccc2)nc2sc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.2 g, 0.75 mmol) and benzonitrile (0.23 g, 2.26 mmol) in dioxane (4 ml) was added 4M HCl in dioxane (4 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with diethyl ether and dried. The solid was redissolved in DMF and the mixture was heated at 100° C. for 3 hours. The solvents were removed under reduced pressure. The residue was diluted with water and the solid was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) to yield the title compound as a white solid (0.20 g, 82%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[C@H:5]([CH2:16][CH2:17][CH3:18])[CH2:4][O:3]1.Cl.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[C@H:5]([CH2:16][CH2:17][CH3:18])[CH2:4][O:3][C:2]4=[O:1])=[CH:15][CH:14]=3)=[O:13])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 28.3 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(2-oxo-4-propyloxazolidin-3-yl)benzoic acid (498 mg) described in Preparation Example 79 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (239 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:23]3[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Product: CCc1cc(-c2cccc(CN3CCC(O)CC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with 4-hydroxypiperidine as described in Method A, Example 123 to give the title compound. MS: m/e=328 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[C:34]1([CH:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:42][CH2:41][CH:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:22])(=[O:15])=[O:16])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: O=C(NCC(c1ccccc1)c1ccccc1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Yield: 28.9 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 39 mg of 2,2-diphenylethylamine. 39 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide are thus obtained in the form of a yellow paste [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.95 (s, 3H), 3.77 (mt, 2H), 3.90 (dd, J=8 and 6.5 Hz, 2H), 4.22 (mt, 2H), 4.42 (t, J=8 Hz, 1H), 4.79 (s, 1H), from 7.10 to 7.40 (mt, 10H), 7.38 (d, J=8.5 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.48 (d, J=8.5 Hz, 4H), 7.70 (mt, 2H), 8.56 (t, J=6.5 Hz, 1H)].
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[S:16][CH:17]=[CH:18][C:3]=12.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32].[N-]=C=O>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([C:31]([NH:30][C:21]3[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=3[F:19])=[O:32])[CH3:15])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[S:16][CH:17]=[CH:18][C:3]=12
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CNc1ccc(N2CN=c3sccc3=C2N)cc1
Agent: [N-]=C=O
Product: CN(C(=O)Nc1cc(C(F)(F)F)ccc1F)c1ccc(N2CN=c3sccc3=C2N)cc1

Procedure:
The compound was prepared following the procedure described in Example 429, substituting 4-amino-3-(4-(methylamino)phenyl)-thieno[2,3-d]pyrimidine as the amine and using 2-fluoro-5-trifluoromethyl-phenyl isocyanate as the isocyanate of choice. MH+=462.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1([N+:12]2[C:17](Cl)=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1([N+:12]2[CH:17]=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Nc1cn[n+](C2CCCCC2)c(Cl)c1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Product: Nc1cc[n+](C2CCCCC2)nc1

Procedure:
The procedure of Example 4 is adopted but without triethylamine and 15.6 parts of 1-cyclohexyl-4-amino-6-chloropyridazinium perchlorate is used. 8.6 parts (62.1% of theory) of 1-cyclohexyl-4-aminopyridazinium perchlorate is obtained; C10H16O4N3Cl, melting point 114° to 116° C after having been recrystallized from water.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[CH2:34]([NH2:37])[CH:35]=[CH2:36]>CO>[OH:1][CH:2]([CH2:3][NH:37][CH2:34][CH:35]=[CH2:36])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: C=CCN
Reactant: O=C(c1ccc(OCCCCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: CO
Product: C=CCNCC(O)CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reaction time: 8 h

Procedure:
1-{1-[4-(4-Oxiranylbutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (4.6 g) is dissolved in methanol (100 ml), and thereto is added allylamine (10 ml), and the mixture is stirred overnight. The reaction mixture is concentrated and purified by silica gel column chromatography (eluent; dichloromethane:methanol=10:1) to give 1-{1-[4-(5-hydroxy-6-allylaminohexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2.5 g) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccc(F)cc2C1=O

Procedure:
3.57 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 6.5 hours with 0.925 g (11 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 165°-167°.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=O.[CH3:8][NH:9][C:10]([NH2:12])=[O:11].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:8][N:9]1[C:1](=[O:7])[CH2:2][C:3](=[O:5])[NH:12][C:10]1=[O:11]
Reactant: CNC(N)=O
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CC(=O)NC1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70° C., acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90° C. for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8%). m.p.=131.2-133.1° C. [Lit.1: m.p.=130-131.5° C.].
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3](OC(C)(C)C)=[O:4].[CH3:45][N:46](C)[C:47](Cl)=O>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([N:46]([CH3:47])[CH3:45])=[O:4]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CN(C)C(=O)Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)N(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and dimethylcarbamoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]([CH:26]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]1)[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]([CH3:17])[CH:26]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]2)=[CH:24][CH:23]=1
Reactant: CN1CCC(N(C)c2ccc(N)cc2)C1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)C1
Yield: 43.2 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine (0.12 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[methyl(1-methylpyrrolidin-3-yl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.12 g, 44%) as a rust colored powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:31][CH2:32]1)[CH3:19]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-ethoxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=428.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1)[C:12]([OH:14])=O.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][C:35]([F:38])([F:37])[F:36])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:36])([F:37])[F:38])[N:25]=2)[CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1
Reactant: COc1cc(C(=O)O)ccc1-c1cscc1C
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1-c1cscc1C

Procedure:
Oxalyl chloride (123 μL; 1.45 mmol; 3 eq.), Intermediate 29 (120 mg; 0.48 mmol; 1 eq.), Intermediate 2 (106 mg; 0.48 mmol, 1 eq.) and DIEA (250 pit; 1.45 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCCOc1cccc(C2=NNC(=O)CC2)c1
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCOc2cccc(C3=NNC(=O)CC3)c2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29](I)=[CH:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]3=[N:25][CH:26]=2)[CH:16]=[N:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46](B2OC(C)(C)C(C)(C)O2)[C:45]([CH3:58])=[N:44]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[CH:16]=[N:17][C:18]([O:19][CH3:20])=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:14]=4)[CH:22]=3)[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]=2)[C:45]([CH3:58])=[N:44]1
Reactant: COc1ncc(-c2cnc3c(c2)c(I)cn3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Yield: 63.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 5-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-6-methoxypyridin-3-yl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 66) (100 mg, 0.155 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (61 mg, 0.186 mmol) using Pd(PPh3)2Cl2 (5 mg, 0.0077 mol) and sodium carbonate (49 mg, 0.465 mmol) in DME/water (10/1 ml) to afford 61 mg (54.5% yield) of the titled compound. MS: m/z=621.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[S:19]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
Into 50 mL of pyridine was dissolved 2.95 g (16.9 mmoles) of 3-tert-butoxycarbonylamino-1-propanol. To the solution, while being cooled in ice under an argon atmosphere, was added dropwise over a period of 40 minutes a solution of 3.36 g (17.7 mmoles) of p-toluenesulfonyl chloride in pyridine. The mixture was left standing overnight at 7° C., then admixed with a small volume of water, and evaporated to dryness. The residue was dissolved in 200 mL of chloroform, washed successively with 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and water, then dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography using 120 g of silica gel (Wako-Gel®C-200) and a toluene-ethyl acetate (8:1 by volume) mixture as developing solvent. Fraction Nos. 35 to 68 (each 15 mL in volume) were combined and evaporated to dryness to yield 3.06 g (55% yield) of O-tosyl-3-tert-butoxycarbonylamino-1-propanol in colorless oily form.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14](O)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].[F:39][C:40]([F:46])([F:45])[C:41]1([NH2:44])[CH2:43][CH2:42]1>>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:44][C:41]3([C:40]([F:46])([F:45])[F:39])[CH2:43][CH2:42]3)=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: NC1(C(F)(F)F)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)nc5)C4)c3)ncnc21
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(c2ccc(C(=O)NC3(C(F)(F)F)CC3)nc2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 12, Step 3 starting from 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylic acid (Example 12, Step 2) and 1-(trifluoromethyl)cyclopropanamine (Oakwood Products, Inc., Cat. #: 038175). LCMS (M+H)+: m/z=508.2. 1H NMR (400 MHz, DMSO-d6): δ 12.69 (br, 1H), 9.12 (s, 1H), 9.11 (d, J=2.9 Hz, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.95 (d, =2.7 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.84-7.80 (br, 1H), 7.26 (dd, J=2.1, 1.3 Hz, 1H), 7.11 (dd, J=8.7, 2.8 Hz, 1H), 4.70 (d, J=9.1 Hz, 2H), 4.44 (d, J=9.2 Hz, 2H), 3.80 (s, 2H), 1.28 (m, 2H), 1.17 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].S(=O)(=O)(O)O.C(Cl)Cl.[OH-].[Na+].[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40]O>>[OH:23][C@H:3]1[C@H:2]([O:1][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH3:34])[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCOCCO
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCCOCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 50 °C

Procedure:
5 g of (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]-naphthyridine are dissolved in 40 ml of 2-(2-methoxyethoxy)ethanol, 3.2 g of sulfuric acid (98% strength) are added and the mixture is warmed at 50° C. for 16 hours. It is then poured onto ice, 100 ml of methylene chloride are added and the mixture is adjusted to pH 7 using aqueous 8 N sodium hydroxide solution. After separation of the organic phase, the aqueous phase is extracted a further two times using 50 ml of methylene chloride each time, the combined organic phases are washed with 100 ml of water, dried over sodium sulfate and the solvent is stripped off in vacuo. The residue is purified on silica gel (eluent: diethyl ether/2-propanol=10/1). 105 mg of the title compound are obtained. 1H-NMR (200 MHz, DMSO): δ=2.25 (s, 3H), 2.33 (s, 3H), 3.23 (s, 3H), 3.32-3.47 (m, 6H), 3.59-3.69 (m, 2H), 3.97-4.07 (q, 1H), 4.44-4.47 (m, 2H), 5.18-5.21 (d, 1 OH), 5.85-5.86 (d, 1NH), 6.74-6.78 (d, 1H), 7.19-7.45 (m, 6H).