Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1O.S([O:21][CH3:22])(OC)(=O)=O.[C:23]([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C>CC(C)=O>[I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH3:23])=[O:13])[C:3]=1[O:21][CH3:22]
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc2c(c(I)c1O)CCCC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(c(I)c1OC)CCCC2
Yield: 88.3 %

Procedure:
To a stirred suspension of 4-iodo-3-hydroxy-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid (23.43 g, 73.65 mmol) in dry acetone (450 mL) was added dimethyl sulfate (17.42 mL, 184.13 mmol) and K2CO3 (25.45 g, 184.13 mmol). The mixture was stirred at reflux overnight, cooled and triethylamine (40 mL) was added. After 0.5 h the mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed successively with 1N HCl (2×50 mL), sat. aqueous sodium bicarbonate (2×50 mL) and brine (50 mL ), dried (Na2SO4), filtered and concentrated in vacuo to afford a brown oil (22.52 g, 90%). 1H NMR (CDCl3) δ 7.56 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.69 (m, 4H), 1.79 (m, 4H). MS m/z 347 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CCO>[CH2:6]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C1CNCCN1
Reactant: C#CCCCOS(C)(=O)=O
Solvent: CCO
Product: C#CCCCN1CCNCC1
Yield: 24 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (19.55 g) and piperazine (41.5 g) in EtOH (80 mL) was heated to reflux for 1 h, and evaporated. The residue was taken in NaOH 2M (70 mL) and extracted with Et2O (70 mL). Evaporation gave 1-(pent-4-ynyl)piperazine (4.4 g).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNCCC(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)CCC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-methylisoamylamine (Matrix) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].S(Cl)([Cl:7])=O.[NH2:9][C@H:10]([C:12](O)=[O:13])[CH3:11]>>[ClH:7].[CH2:1]([O:4][C:12](=[O:13])[C@H:10]([CH3:11])[NH2:9])[CH2:2][CH3:3]
Reactant: CCCO
Reactant: C[C@H](N)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCOC(=O)[C@H](C)N
Product: Cl
Yield: 94.6 %

Procedure:
This was synthesised according to Standard Procedure 1, using anhydrous propan-1-ol (42.0 ml, 0.56 mol), thionyl chloride (8.2 ml, 0.112 mol) and L-alanine (5.0 g, 0.056 mol). The product was isolated as a white solid (8.88 g, 94.3%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
Methanesulphonyl chloride (2.5 g) was added dropwise to a stirred solution of 1-benzyl-4-aminopiperidine (4 g) and triethylamine (4 ml) in chloroform (40 ml) at room temperature. After 20 minutes, water (40 ml) was added, the organic layer separated, dried (MgSO4), and evaporated in vacuo to give an oil which crystallized from ether to give N-(1-benzylpiperid-4-yl)methanesulphonamide (2 g, m.p. 135°-6°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[N:30]([C:31]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)=[O:32])[CH2:29][CH2:28][N:10]2[C:11](=[O:27])[C:12]2[N:13]([CH:15]=[C:16]([N:18]4[CH:22]=[C:21]([Si](C)(C)C)[N:20]=[N:19]4)[CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.O.C([O-])(O)=O.[Na+]>C(O)(=O)C.O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[N:30]([C:31]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)=[O:32])[CH2:29][CH2:28][N:10]2[C:11](=[O:27])[C:12]2[N:13]([CH:15]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[N:19]4)[CH:17]=2)[CH2:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(C23Cn4cc(-n5cc([Si](C)(C)C)nn5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C23Cn4cc(-n5ccnn5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 60 °C
Yield: 41.4 %

Procedure:
10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (10.6 mg, 0.012 mmol) was dissolved in a mixture of acetic acid/water/THF (3:1:1; 1 mL). The mixture was stirred at 60° C. When the reaction was complete (48 hours; monitored by LCMS) water was added followed by a saturated aqueous solution of NaHCO3. The mixture was then extracted with EtOAc (3 times) and the organics washed with brine, dried (Na2SO4), filtrated and concentrated in vacuo. The resulting material was purified by flash chromatography (Silica gel, EtOAc/Hex 3:1 followed by 100% EtOAc) to give compound 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-(1H-1,2,3-triazol-1-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (113) as a white solid (2.28 mg, yield 25%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([OH:22])=O)=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][C:36]2=[O:44])[CH2:31][CH2:30]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:37][C:36]4=[O:44])[CH2:31][CH2:30]3)=[O:22])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12
Reactant: O=C1Cc2ccccc2N1C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12)N1CCC(N2C(=O)Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a suspension of 0.10 g (0.31 mmol) 6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid and one drop of DMF in 2 ml dichloromethane were added dropwise at 0° C. 0.032 ml (0.37 mmol) oxalyl chloride. The mixture was allowed to warm to room temperature, stirred for 1 h and subsequently added dropwise to a solution of 74 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydro-indol-2-one and 63 mg (0.62 mmol) triethylamine in 1 ml dichloromethane at room temperature. After stirring over night the reaction mixture was concentrated and the residue was purified by flash chromatography to give 78 mg (48%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[CH:25]([CH2:29][CH2:30][CH2:31][CH3:32])[C:26](Br)=[O:27]>O>[CH2:29]([CH:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH2:30][CH2:31][CH3:32]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CCCCC(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 4.6 (15), 5177-5186 (1990)] (8.0 g) in a mixed solvent of ethyl acetate (200 ml) and water (200 ml) were added sodium hydrogen carbonate (11.18 g) and 2-bromohexanoyl bromide (12.73 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (300 ml), to the solution was added potassium carbonate (6.0 g) and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting crystals were recrystallized from ether to give 2-butyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.3 g).
Reaction SMILES: [OH-].[Na+].O.[CH:4]1([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[S:18]([NH2:21])(=[O:20])=[O:19])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH:22]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CC(C)=O>[CH:4]1([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[S:18]([NH:21][C:30]([NH:29][CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:31])(=[O:20])=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: NS(=O)(=O)c1cnccc1NC1CCCCCC1
Reactant: O=C=NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCCC1)NS(=O)(=O)c1cnccc1NC1CCCCCC1

Procedure:
0.01 mol of NaOH in solution in a minimum of water is added to a solution of 2.4 g of (4-(cycloheptylamino)pyrid-3-yl)sulphonamide in 80 cm3 of a mixture of water and acetone (1/1). Stirring is effected with a bar magnet and 2.1 g of cycloheptyl isocyanate are added. Stirring is continued while monitoring the progress of the reaction by thin layer chromatography. Evaporation is carried out in vacuo and the residue is taken up in 100 cm3 of 0.2N NaOH. After filtering, the pH of the solution is adjusted to 6.5 and the resulting precipitate is suction-filtered and then dried. The N-{[4-(cycloheptylamino)pyrid-3-yl]sulphonyl}-N'-(cycloheptyl)urea so obtained may optionally be recrystallised from an aqueous alcoholic solution.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(OCC)(=O)C>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][N:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CCCCCBr
Reactant: COc1ccc(S(=O)(=O)NCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCN(CCO)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 24 h
Yield: 81.8 %

Procedure:
Part A: To a solution of 2.0 g (8.6 mmol) of N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide from Example 1 in 20 mL of anhydrous DMF, was added 3.58 g (25.9 mmol) of powdered potassium carbonate and then 1.96 g (13 mmol) of 1-bromopentane. After 24 hours, ethyl acetate and water was added, the organic layer separated and washed 3×s with brine, dried with sodium sulfate, filtered and stripped to afford 2.3 g of crude product. This was chromatographed on 150 g of silica gel using 20%-50% ethyl acetate/hexane to afford 2.12 g of the desired N-(hydroxyethyl)-N-pentyl-4-methoxybenzenesulfonamide, m/e=302 (M+H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[C:1]1([C:7]#[C:8][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: BrCCCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C(#Cc1ccccc1)CCCCCCOC1CCCCO1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 11.2 g of phenylacetylene dissolved in 100 ml of tetrahydrofuran, 78.8 ml of 1.6M-hexane solution of n-butyl lithium was added dropwise at 5°-8° C. Then 150 ml of a hexamethylphosphoramide solution containing 29.4 g of 1-bromo-6-(2-tetrahydropyranyloxy)-hexane was added dropwise at 10°-20° C. After stirring at 20° C. for 30 minutes, the reaction mixture was poured into ice-water and extracted with hexane. The organic layer was washed with water, dried and then the organic solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate=10:1), to give 18.3 g of 1-phenyl-8-(2-tetrahydropyranyloxy)-1-octyne as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][C:7]([C:20](OCC)=[O:21])=[CH:6][N:5]2[C:25]=1[CH3:26].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:18])=[CH:8][C:7]([CH2:20][OH:21])=[CH:6][N:5]2[C:25]=1[CH3:26]
Reactant: CCOC(=O)c1cc(NCc2c(C)cccc2C)c2nc(C)c(C)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CNc1cc(CO)cn2c(C)c(C)nc12
Yield: 66.5 %

Procedure:
To a stirred solution of ethyl 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (1.2 g, 3.4 mmol) in tetrahydrofuran (30 ml) was added LiALH4 (0.7 g, 18.5 mmol) during 20 min. at 5° C. 0.7 ml of water was added dropwise, followed by 0.7 ml of 15% sodium hydroxide and then 2.1 ml of water. The solids were removed by filtration and washed thoroughly with methylene chloride: methanol (1:1). The filtrate and washings were combined and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent. Treating the residue with diethyl ether and filtration gave 0.7 g (67%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1.[NH3:24].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(F)c(C(C)C)n1
Solvent: CO
Product: CC(C)c1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1F
Temperature: 40 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of ethyl 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (290 mg, 856 μmol) was added 7N ammonia in MeOH (12.2 mL, 85.6 mmol). The mixture was stirred at 40° C. for 18 h, after which the solvent was removed to give 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 94%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.86 (s, 1H), 9.26 (s, 1H), 8.19 (br. s, 1H), 7.36 (t, J=8.8 Hz, 1H), 6.79 (dd, J=8.5, 2.8 Hz, 1H), 5.70 (br. s, 1H), 3.45 (m, 1H), 1.37 (d, J=6.7 Hz, 6H).
Reaction SMILES: [C:1](/[N:4]=[N:5]/[C:6](N)=[O:7])(N)=[O:2].[OH-:9].[K+:10].[OH2:11]>>[N:5]([C:6]([O-:7])=[O:11])=[N:4][C:1]([O-:9])=[O:2].[K+:10].[K+:10]
Reactant: NC(=O)/N=N/C(N)=O
Reactant: [OH-]
Reactant: O
Agent: [K+]
Product: O=C([O-])N=NC(=O)[O-]
Temperature: 0 °C

Procedure:
Azodicarbonamide (5.0 g) was stirred with a solution of potassium hydroxide (7.0 g) in water (12 ml) at 4°. After stirring in the ice bath for 1 h the mixture was diluted with ice/water (30 ml) and the solution was filtered. The filtrate was diluted with cool (2°) ethanol (100 ml) and the resultant solid was filtered off, washed with ethanol, methanol and ether to give potassium azodicarboxylate (6.9 g). This was then mixed with 3-aza-2-oxabicyclo[2.2.1]hept-5-ene-3-carboxylic acid, (phenylmethyl) ester (0.82 g) in dry pyridine (60 ml), and acetic acid (2.02 g) was added with stirring at room temperature. After one hour a further portion of glacial acetic acid (2.02 g) was added and the reaction mixture was stirred for 15.5 h. The mixture was evaporated to dryness under reduced pressure. Further acetic acid was then added to quench the remaining yellow colour of the diimide precursor. The residue was partitioned between 0.5M citric acid (75 ml) and ethyl acetate (75 ml) and the organic phase was separated, dried, and concentrated in vacuo. The residue was purified by FCC eluting with ethyl acetate:cyclohexane (1:2) to give the title compound (0.69 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=2)[C:30](=[O:38])[NH:29]1)=O)(C)(C)C.O>CN1C(=O)CCC1>[CH:18]([C:16]1[CH:17]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:37][C:34]3[CH:35]=[C:36]4[C:31]([C:30](=[O:38])[NH:29][NH:28]4)=[CH:32][CH:33]=3)[N:11]=2)[NH:14][N:15]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: CC(C)c1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(Nc2nc(Nc3ccc4c(=O)[nH][nH]c4c3)nc3ccccc23)[nH]n1
Temperature: 130 °C

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(5-isopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.17 mmol) in NMP (1 mL) was added 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (65 mg, 0.26 mmol). The mixture was heated at 130° C. for 3 hrs, cooled to room temperature, and then poured into water. The crude material was collected by filtration and treated with TFA in CH2Cl2 for 30 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:14])[CH2:12][Cl:13])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:15])[CH:9]=[C:10]([C:11](=[O:14])[CH2:12][Cl:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(C(=O)CCl)ccc12
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C(=O)CCl)cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-chloroethanone (500 mg, 2.37 mmol) in DMF (40 mL) at −40° C., was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (339 mg, 1.19 mmol). The reaction was allowed to stir for 1 hr while warming to rt. A precipitate had formed and the reaction was filtered and the precipitate was washed With Et2O to afford 360 mg (52%) of the desired product as a white powder. 1H NMR (300 MHz, DMSO-d6) 8.12 (s, 1 H), 7.53 (s, 1 H), 5.10 (s, 2H); LC-MS (m+H]+=291, RT=2.51 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26].CN(C=O)C.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=3)=[CH:21][N:22]=2)[N:19]=1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A reaction vial was charged with (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 30 mg, 0.095 mmol), 4-(methylsulfonamido)benzoic acid (41 mg, 0.19 mmol), and 2(1H-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophophate methanaminium (HATU; 72 mg, 0.19 mmol). DMF (0.8 mL) was added to the mixture to make a solution. The reaction mixture was cooled in an ice bath for 10 minutes before DIEA (0.05 mL, 0.29 mmol) was added dropwise. After addition, reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water and brine (10 mL each), and concentrated. The crude material was purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(methylsulfonamido)benzamide as a yellowish solid (13 mg, 27% yield). MS (apci negative) m/z=511.4 (M−H).
Reaction SMILES: C(#N)C.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH2:18][C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH2:29]([NH:31][NH2:32])[CH3:30]>O>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:31]([CH2:29][CH3:30])[N:32]=[C:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCNN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Solvent: CC#N
Solvent: O
Product: CCn1nc(Cc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 19 °C
Reaction time: 1 h

Procedure:
A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer, internal heating coil, 5 L dropping funnel, and thermocouple was charged with the acetonitrile (39 L) and 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione 4 (3.00 Kg, 8.68 mol). To the resulting clear light yellow solution was added water (18.6 l). The mixture was warmed to 19° C. and the mixture became clear. An ethyl hydrazine solution (35% in water, 1.66 Kg, 1.71 L, 9.55 mol) was added via a dropping funnel over 100 min. The batch temperature after the addition was 20° C. The reaction solution was aged for 1 h at 20 □ C then checked for completion by HPLC. If any 4 remained, additional ethyl hydrazine was added to complete the reaction. At the end of reaction the ratio of products 5:6:7 is 83.6:14.3:2.1 with complete consumption of 4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[O:12][C:8]=2[CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:16]1([C:14]([NH:13][C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)[CH:20]=[CH:19][C:9]=3[N:10]=2)=[O:15])[CH2:18][CH2:17]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzooxazol-2-yl]cyclopropanecarboxamide (128 mg, 415 μmol) in pyridine (3 mL) were added a solution of 3-(trifluoromethyl)benzoyl chloride prepared above in pyridine (2 mL) and N,N-dimethylpyridine-4-amine (58.9 mg, 482 μmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL) and ethyl acetate (100 mL). This solution was washed with 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→80/20) to give the title compound (101 mg, 50%) as a colorless solid.