Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([NH2:13])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]#[N:13]
Reactant: Cc1nc2ccccn2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nc2ccccn2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a mixture of 2-methylimidazo[1,2-a]pyridine-3-carboxamide (3.50 g, 20 mmol) produced above, pyridine (4.85 mL, 60 mmol) and tetrahydrofuran (50 mL) was added dropwise a solution of trifluoroacetic anhydride (4.24 mL, 30 mmol) in tetrahydrofuran (10 mL) under ice-cooling. The mixture was stirred at room temperature for 1 hr, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate/diisopropyl ether to give the title compound (2.5 g, 80%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[CH:25]3[CH2:26][NH:27][CH2:28][CH:21]2[CH2:22][O:23][CH2:24]3)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.C[O:35][C:36]([C:38]1[C@H:39](C2C=CC(F)=CC=2Cl)N=C(C2SC=CN=2)N[C:43]=1CN1C2CN(C(=O)C)CC1COC2)=[O:37].CN([C:73]([O:77]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[C@@H:25]3[CH2:26][N:27]([C:73](=[O:77])[C:38]([CH3:43])([CH3:39])[C:36]([OH:35])=[O:37])[CH2:28][C@H:21]2[CH2:22][O:23][CH2:24]3)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)C1=C(CN2C3CNCC2COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: COC(=O)C1=C(CN2C3COCC2CN(C(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CN(C(=O)C(C)(C)C(=O)O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
A mixture of methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (50 mg, 0.1 mmol), 2,2-dimethylpropanedioic acid (prepared as shown in Example 15) (26.4 mg, 0.2 mmol), HATU (48 mg, 0.25 mmol) and triethyl-amine (0.09 mL, 0.625 mmol) in dichloromethane (5 mL). The mixture was stirred at 25° C. for 16 h, and then concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford 10 mg of the title compound as a white powder (yield was 18%).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].[H][H]>[Pt]=O.C(O)C>[CH2:19]([NH:23][CH:11]1[CH2:12][C:13]([CH3:15])([CH3:14])[N:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]([CH3:18])([CH3:17])[CH2:10]1)[CH2:20][CH2:21][CH3:22]
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: CCCCN
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 92.7 %

Procedure:
A mixture of 9.5 grams (37.5 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one, 13.7 grams (187 mmol) of n-butylamine, 0.4 gram of platinum oxide, and 120 ml of ethanol is hydrogenated on a Parr apparatus (50 psi, ambient temperature) till hydrogen uptake ceases. The catalyst is removed by filtration and the filtrate is evaporated to afford 10.8 grams (93% yield) of the title compound as a colorless syrup.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: CN1CCN(C(=O)c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Reactant: OB(O)c1ccc(F)cc1F
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: [K+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(Nc3nc(-c4ccc(F)cc4F)ccc3C(N)=O)cc2)CC1
Temperature: 90 °C
Yield: 35.2 %

Procedure:
A mixture of 6-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)nicotinamide (40 mg, 0.107 mmol), 2,4-difluorophenylboronic acid (16.90 mg, 0.107 mmol), K2CO3 (29.6 mg, 0.214 mmol), and Pd(Ph3P)4 (12.36 mg, 10.70 μmol) in THF (2 mL) in a microwave vial was degassed by passing nitrogen through briefly. The vial was sealed and heated to 90° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd. NaHCO3, water, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, basified by 1N NaOH, extracted with CH2Cl2, washed with water, concentrated to give 17 mg of 6-(2,4-difluorophenyl)-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)nicotinamide as a yellow solid. LCMS: (M+H)+=452.08 1H NMR (400 MHz, CDCl3) δ ppm 10.80 (1H, s), 8.08 (1H, td, J=8.79, 6.59 Hz), 7.79-7.83 (1H, m), 7.77 (2H, d, J=8.35 Hz), 7.35 (2H, d, J=8.79 Hz), 7.23-7.27 (1H, m), 6.98-7.06 (1H, m), 6.93 (1H, ddd, J=11.42, 8.79, 2.64 Hz), 3.67 (4H, br. s.), 2.36-2.61 (4H, m), 2.33 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([NH:16][CH2:17][C:18]#[CH:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[C:20]([NH:30][CH2:31][C:32]#[CH:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(OCC)(=O)C>C(NC(C)C)(C)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>[C:12]([O:11][C:9]([NH:16][CH2:17][C:18]#[C:19][C:2]1[N:3]=[CH:4][C:5]([C:33]#[C:32][CH2:31][NH:30][C:20](=[O:21])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][CH:7]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: C#CCNC(=O)OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(C#CCNC(=O)OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A mixture of 2,5-dibromopyridine (1.19 g), N-Boc-propargylamine (781 mg), Pd(PPh3)2Cl2 (73 mg), and CuI (10 mg) in diisopropylamine (20 mL) was stirred at room temperature overnight under nitrogen atmosphere. To the mixture was added N-Cbz-propargylamine (1.14 g) and the mixture was heated under reflux temperature for 5 hours under nitrogen atmosphere. The mixture was cooled to room temperature. To the mixture was added ethyl acetate (50 mL). The precipitates were filtered and washed with ethyl acetate. The filtrate and washings were combined and purified by silica gel column to give 6-1 (250 mg) as a crystalline compound.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Br:31][CH2:32][C:33](Br)=[O:34]>C(Cl)Cl>[Br:31][CH2:32][C:33]([NH:11][CH2:10][CH2:9][S:8][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:34]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution S-triphenylmethyl-2-aminoethanethiol (48 g, 0.15 mol) and Et3N (20.9 ml, 0.15 mol) in DCM (180 ml) was slowly added to a stirred solution of bromoacetyl bromide (13.9 ml, 0.15 mol) in DCM (100 ml) at a temperature of -20° C. The reaction was allowed to warm to room temperature over a one hour period. The reaction was washed with 500 ml portions of H2O, 0.2N HCl, saturated NaHCO3, and saturated NaCl. The organic solution was dried (MgSO4) and concentrated to an oil. This oil was crystallized from DCM-hexane to give product (54.9 g, 83%) as a colorless solid, MP 137°-139.5° C. (J. A. Wolff, Ph.D. Thesis, Massachusetts Institute of Technology, February 1992, MP 130°-135° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[N:34]1[C:42]2[C:37](=[CH:38][C:39]([C:43]3[N:47]=[CH:46][N:45]([C:48]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:44]=3)=[CH:40][CH:41]=2)[C:36]([C:67]2[CH:68]=[C:69]([NH2:73])[CH:70]=[CH:71][CH:72]=2)=[N:35]1>ClCCl>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:73][C:69]1[CH:70]=[CH:71][CH:72]=[C:67]([C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[C:39]([C:43]4[N:47]=[CH:46][N:45]([C:48]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)[C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[N:44]=4)[CH:38]=3)[N:34]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)[N:35]=2)[CH:68]=1)=[O:6]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethylamino)acetic acid hydrochloride (0.077 g, 0.55 mmol) in 5 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.105 g, 0.55 mmol) and triethyl amine (0.077 mL, 0.55 mmol). The reaction was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.300 g, 0.498 mmol), dissolved in 1 mL of dichloromethane was added to the solution. The reaction was stirred at room temperature overnight. Further conversion was promoted by reacting an additional equivalent of reagents and stirring at room temperature for 12 hours. The reaction mixture was then partitioned between water and dichloromethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 688 [M+H]+.
Reaction SMILES: C(OC1C=C2[C:11](=[CH:12][C:13]=1C)[N:10]([C:15](=O)[CH3:16])N=C2)(=O)C.[CH3:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[OH:28]>>[CH3:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[O:28][CH:13]1[CH2:12][CH2:11][NH:10][CH2:15][CH2:16]1
Reactant: CC(=O)Oc1cc2cnn(C(C)=O)c2cc1C
Reactant: Cc1cc2[nH]ncc2cc1O
Product: Cc1cc2[nH]ncc2cc1OC1CCNCC1

Procedure:
The following compound of Example 406 was synthesized by carrying out reactions according to the methods described in Example 372, (b) and Example 377, except for using the 6-methyl-1H-indazol-5-ol synthesized in Example 403, as a starting material.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]O)=[CH:5][CH:4]=1.[BrH:14]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:14][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(CCBr)cc1

Procedure:
A mixture of step 2-(4-trifluoromethylphenyl)-ethanol (10 g, 0.053 mol, from step (iii) above), 86 ml (1.06 M) HBr in acetic acid and 10 ml sulfuric acid was stirred at 100° C. for 4 h. The reaction mixture was poured into ice and extracted with diethylether. The organic layer was washed with NaHCO3, water and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using petroleum ether as eluent afforded 5 g of the title compound as a liquid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:13]2[C@@H:8]([S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12]2)[CH2:7][C@H:6]1[O:21]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:21][C@@H:6]1[CH2:7][C@@H:8]2[S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C@@H:13]2[C@H:5]1/[CH:4]=[CH:3]/[C@@H:2]([OH:1])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Reaction time: 2 h
Yield: 44.7 %

Procedure:
The compound 13 (220 mg) was dissolved in methanol (1.1 mL), a p-toluenesulfonic acid monohydrate (20 mg) was added at room temperature, and the mixture was stirred for 2 hours. The residue obtained by concentration of the reaction liquid under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→ethyl acetate) to obtain a titled compound (82 mg) having the following physical property values.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1.S(Br)([Br:16])=O>O1CCOCC1.C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:16])=[CH:8][CH:7]=1
Reactant: OCc1ccc(OCCCCl)cc1
Reactant: O=S(Br)Br
Solvent: C1COCCO1
Solvent: CCOCC
Product: ClCCCOc1ccc(CBr)cc1
Reaction time: 0.17 h

Procedure:
A solution consisting of 4-(3-chloropropoxy)-benzyl alcohol No. 162 (10.6 g, 52.8 mmol) in dioxane (0.125 l) was cooled to 0° C. and treated with a dropwise addition of thionyl bromide (12.0 g, 58.0 mmol). After 10 minutes the reaction was complete. The dioxane was diluted with ethyl ether and washed with water, brine, and then dried over MgSO4. The material was concentrated down to yield 15 g of an oil: 1H NMR (DMSO) 7.36 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.6 Hz), 4.68 (s, 2H), 4.08 (t, 2H, J=5.9 Hz), 3.77 (t, 2H, J=6.4 Hz); MS (FAB) 266 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)CC)C.ClC(OC)=O.C[NH-]>C(Cl)(Cl)Cl>[CH3:16][NH:18][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: C[NH-]
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cnc2cccc(C)n2c1=O

Procedure:
A solution containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. while stirring and cooling by ice-salt. To this mixture, 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml chloroform are dropped at -20° C. during 10 minutes. After stirring for 5 minutes, a solution containing 2.5 g (0.08 mol) of methylamide (prepared from methylamine hydrochloride in chloroform by adding triethylamine) in 80 ml of chloroform is added dropwise to the reaction mixture at -18° C. during 30 minutes. After stirring below -10° C. for 1 hour, the reaction mixture is allowed to stand in the refrigerator overnight. Next day the reaction mixture is washed 3 times with 140 ml of 5% sodium hydrogen carbonate solution each and then with 140 ml of water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is stirred with 150 ml of 10% hydrochloric acid at room temperature for 1 hour, then the precipitated starting material, 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid weighing 10 g is filtered off. The pH value of the aqueous filtrate is adjusted to 9 by adding 20% sodium hydroxide solution and then extracted 3 times with 100 ml of chloroform each. The combined organic phase is dried over anhydrous sodium sulfate and evaporated. After recrystallization of the residue from ethanol, 3.2 g (45.5%) of the name lemon-yellow product are obtained, m.p.: 208°-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[OH2:10]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: O
Reactant: Cc1cc(Cl)ccc1Br
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cc(Cl)ccc1Br
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To the solution of 2-bromo-5-chlorotoluene (25 g) in acetic anhydride (100 ml) and sulfuric acid (20 ml) was added dropwise chromium(VI) oxide (36.5 g) in acetic anhydride (200 ml) for 3 hours at -15° C. The mixture was stirred for 1 hour at -5° C. and then poured into ice-cooled water, and extracted with ether. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was suspended in ethanol (100 ml) and 3N-HCl (200 ml) and refluxed for 1 hour. After removal of the solvent, water was added to the residue, and extracted with ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:12]OS(C1C=CC(C)=CC=1)(=O)=O)[C:10]#[N:11].C(N(CC)CC)C.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:32][SH:33]>C(O)C>[NH2:11][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[N:12][S:33][C:32]=1[C:31]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)CS
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1snc(-c2ccc(Cl)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
In ethanol (100 ml), (2,4-dichlorophenyl)-O-(p-toluenesulfonyl)hydroxyiminoacetonitrile (10.0 g, 27.1 mmol) prepared in the Step 27-1-2 was dissolved, and triethylamine (3.0 g) and ethyl thioglycolate (4.72 g) were added thereto. The mixture was stirred for one hour at a room temperature. The solvent was distilled off. The residue was dissolved in diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (4.81 g, 56%).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[Br:11][C:12]1[C:13]([NH:18][NH2:19])=[N:14][CH:15]=[CH:16][CH:17]=1>CN1C(=O)CCC1>[Br:11][C:12]1[C:13]([N:18]2[C:2]3=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]3[CH:4]=[N:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: NNc1ncccc1Br
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Brc1cccnc1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 74.8 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added 2-fluoro-4-iodonicotinaldehyde (725 mg, 2.89 mmol), 3-bromo-2-hydrazinylpyridine (543 mg, 2.89 mmol) and anhydrous NMP (Volume: 4.0 mL). The reaction mixture was flushed with argon, securely capped, and heated to 185° C. for 45 min. The reaction mixture was worked up according to the procedure described in Intermediate 69A and the crude product was purified by Biotage Silica gel chromatography using a 12 g Thompson Single Step™ silica cartridge with a linear gradient from 100% CH2Cl2 to 100% ethyl acetate over 11 column volumes to give 867.4 mg (74.9%) of the title compound as a yellow solid. 1H NMR (500 MHz, CCl3D) δ ppm 8.64 (1 H, dd, J=4.58, 1.53 Hz), 8.09-8.25 (3 H, m), 7.65 (1 H, d, J=4.58 Hz), 7.37 (1 H, dd, J=7.93, 4.58 Hz). LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 400.81, 402.81.
Reaction SMILES: N[C@H]1CCCC[C@H]1N[C:9]1[N:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=2)[CH:10]=1.N[C@@H]1CCOC[C@@H]1NC(=O)OC(C)(C)C.[Cl-:45].[Na+].O>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:45][C:9]1[N:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=2)[CH:10]=1
Reactant: [Cl-]
Reactant: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1C(C)C
Agent: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C(C)C
Temperature: 140 °C

Procedure:
To a solution of 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (199 mg, 618 μmol, prepared as described in example 32) in NMP (2.06 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (536 mg, 2.47 mmol) in four portions approximately every 12 h and the mixture heated at 140° C. After 48 h total heating time the mixture was cooled and then diluted with ethyl acetate and brine. The phases were separated then the organic phase was washed with brine (2×), then concentrated in vacuo and the residue obtained was purified by chromatography (silica, 10 to 50% methanol in dichloromethane) to give 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (199 mg, 618 μmol, quantitative) as a light brown solid. MS (EI/CI) m/z: 502.2 [M+H].
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[S:4].[IH:15].[CH3:16]I>CO>[IH:15].[IH:15].[CH3:1][NH:2][C:3](=[N:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[S:4][CH3:16]
Reactant: CNC(=S)NCCCCc1nccs1
Reactant: CI
Agent: I
Solvent: CO
Product: CNC(=NCCCCc1nccs1)SC

Procedure:
N-Methyl-N'-[4-(2-thiazolyl)butyl]thiourea was converted into its hydriodide salt with 66% hydriodic acid. This salt was dissolved in methanol, methyl iodide added and the solution heated under reflux for 2 hours. Concentration and crystallisation of the resultant oil gave N,S-dimethyl-N'-[4-(2-thiazolyl)butyl]isothiourea dihydriodide. Reaction of this isothiourea with hydroxylamine by the procedure of Example 1(ii) gave the title product.
Reaction SMILES: Br[C:2]1[C:6](C)=[CH:5][S:4][CH:3]=1.[Li][CH2:9]CCC.C(O[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(C)C>>[CH3:24][C:19]1([CH3:25])[C:20]([CH3:23])([CH3:22])[O:21][B:17]([C:6]2[CH:2]=[CH:3][S:4][C:5]=2[CH3:9])[O:18]1
Reactant: Cc1cscc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: [Li]CCCC
Product: Cc1sccc1B1OC(C)(C)C(C)(C)O1
Yield: 26 %

Procedure:
Using a procedure similar to Example 4, step (b), 3-bromo-4-methylthiophene (571 mg, 3.2 mmol) was treated with n-BuLi (1.41 mL, 2.5M/hexanes) and then allowed to react with 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (775 μL, 3.8 mmol) to afford 189 mg (26%) of the title compound as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 1.32 (s, 12H), 2.42 (s, 3H), 6.90-6.91 (m, 1H), 7.84 (d, 1H, J=2.9 Hz).