Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=C[C:5](Cl)=[N:6][CH:7]=1.[OH:9][CH2:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[H-].[Na+].O.C[N:25](C)C=O>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:9][CH2:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:25][CH:3]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)COc1ncc(Br)cn1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
In N,N-dimethylformamide (10 mL) were dissolved 5-bromo-2-chloropyridine (1000 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (991 mg), and 60% sodium hydride (248 mg) was added to the solution under ice-cooling. The reaction mixture was stirred at room temperature for 6 hours, at 50° C. for 1 hour and 45 minutes, and then, at room temperature overnight. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtain tert-butyl 3-(5-bromopyrimidin-2-yl)oxy-2,2-dimethylpropanoate (1.048 g).
Reaction SMILES: [C:1]([NH:5][S:6]([NH:9][C:10]([CH2:13][C:14]([CH3:17])([CH3:16])C)([CH3:12])[CH3:11])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(N)(N)(=O)=O.ClO[C:25](C)([CH3:27])[CH3:26].[H-].C(N=NC(CC(C)(C)C)(C)C)(C)(C)C>>[C:1]([NH:5][S:6]([NH:9][C:10]12[CH2:11][CH:26]3[CH2:25][CH:27]([CH2:16][CH:14]([CH2:17]3)[CH2:13]1)[CH2:12]2)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)NC(C)(C)C
Reactant: CC(C)(C)OCl
Agent: CC(C)(C)CC(C)(C)N=NC(C)(C)C
Agent: NS(N)(=O)=O
Agent: [H-]
Product: CC(C)(C)NS(=O)(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 45 %

Procedure:
Treatment of tertiary alcohols with chlorosulfonyl isocyanate gives monoalkyl sulfamyl chlorides (J. B. Hendrickson and J. Joffe, J. Am Chem. Soc., 95, 4084, 1973). Timberlake used this method to synthesize N-tert-butyl-N'-tert-octylsulfamide in 44% yield (J. W. Timberlake, M. L. Hodges and A. W. Garner, Tetrahedron Lett., 3843, 1973 and J. W. Timberlake, J. Alender, A. W. Garner, M. L. Hodges, C. Ozmeral and S. Szilagyi, J. Org. Chem., 46, 20282, 1981). The sulfamide was oxidized with tert-butyl hypochlorite and sodim hydride to tert-butyl tert-octyldiazene. N-tert-Butyl-N'-(adamant-l-yl) sulfamide was prepared in 45% yield by the same route. There is no evidence it was oxidized to the azo. Apparently, tert-butyl tert-2,2,4,6,6-pentamethyl-4-heptyldiazene was also prepared by this route (J. W. Timberlake and A. W. Garner, J. Org. Chem., 41, 1666, 1976).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:24]2[CH:29]=[CH:28][C:27](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=2)[C:3]=1[C:4]#[N:5].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C=O)C>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:24]2[CH:29]=[CH:28][C:27]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(-c2ccc(Cl)c([N+](=O)[O-])c2)cc(-c2ccccc2OCc2ccccc2)nc1N
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(N3CCCC3)c([N+](=O)[O-])c2)cc(-c2ccccc2OCc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a cold (0° C.) solution of 2-amino-6-(2-benzyloxyphenyl)-4-(4-chloro-3-nitrophenyl)nicotinonitrile (1.000 g, 2.189 mmol) in DMF (10 mL) was added pyrrolidine (0.778 g, 10.943 mmol). The mixture was stirred at room temperature for 2 hrs. and then at 60° C. for 2 hrs. The reaction mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in ethanol, and the precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 2-amino-6-(2-benzyloxyphenyl)-4-[3-nitro-4-(1-pyrrolidinyl)phenyl]nicotinonitrile as a yellow solid (0.990 g, yield 92%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1)(=O)[CH3:2].C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[CH3:2][C:1]1[C:8]2[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][N:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CC(=O)NCCc1cn(-c2ccccc2)c2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CC1=NCCc2c1n(-c1ccccc1)c1ccccc21

Procedure:
A mixture of 40.8 g. N-acetyl-1-phenyltryptamine (IIIa), 800 ml. dry benzene and 220 g. phosphorus oxychloride is refluxed for 1 hour. After cooling, the reaction mixture is poured into two liters of cold water with continued stirring and cooling for 1.5 hours. The organic layer is separated, washed twice with water and the aqueous fractions combined and backwashed once with ethyl acetate. The aqueous extract (total volume 3 liters) is treated with one liter of 10% NaOH, followed by one liter of 50% NaOH while stirring and cooling in an ice bath. The product precipitates from the cooled solution and is filtered and washed well with water to remove any co-precipitated inorganic material. Upon drying, 34 g. of 4,9-dihydro-1-methyl-9-phenyl-3H-pyrido[3,4-b]indole, (IVa), m.p. 110°-112° C. is obtained. An analytical sample had a m.p. 110°-112° C. (benzene-petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH3:21])=[N:16][O:17][C:18]=2[CH:19]=O)=[O:7])=[CH:4][CH:3]=1.[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH:30](/[N:31]=[CH:19]/[C:18]1[O:17][N:16]=[C:15]([CH3:21])[C:14]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:7])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1noc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1noc(/C=N/C(c2ccccc2)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a round bottomed flask was added 4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazole-5-carbaldehyde (3.86 g, 11.85 mmol), DCM (50 mL), diphenylmethanamine (2.143 mL, 12.44 mmol), and Na2SO4 (5.05 g, 35.5 mmol). The reaction was stirred at room temperature overnight before being filtered and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (5.61 g, 11.43 mmol) as pale yellow foam. LC/MS m/z 491 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([O:23]C)=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].C1COCC1.[Li+].[OH-].Cl>O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([OH:23])=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Yield: 97 %

Procedure:
Methyl 4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-6-nitroquinazoline-8-carboxylate (190 mg, 0.43 mmol) was treated with a mixture of 650 μL of THF and 650 μL of 2N LiOH (1.3 mmol, 3 equiv.)) at rt for 2 h. Water was added and pH was adjusted to ˜4 with 2N HCl. The precipitate was collected as the desired acid by filtration, and washing with water in 97% yield. 1HNMR (in DMSO): 4.95 (s, 2H), 7.69-7.74 (m, 2H), 7.94 (d, J=1.4 Hz, 1H), 8.81 (s, 1H), 9.02 (d, J=2.2 Hz, 1H), 9.62 (d, J=2.5 Hz, 1H). Mass: M+H+: 427.
Reaction SMILES: F[C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[CH:14]=[C:12]3[C:13]4[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]3=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=4[C:3]=2[Cl:20])[CH2:22][CH2:23]1
Reactant: CC1CCc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1COCCN1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(Cl)c(N3CCOCC3)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 5 h
Yield: 20.9 %

Procedure:
An autoclave containing a mixture of 3 g of 9-fluoro-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 8 g of morpholine and 30 ml of hexamethylphosphoric triamide was immersed in an oil bath at 190° C. and reaction was continued for 5 hours. After completion of reaction, the reaction mixture was cooled to precipitate crystals which then were collected by filtration. The crystals thus obtained were recrystallized from dimethylformamide to give 0.77 g of 9-morpholino-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 271° to 274° C., white rhombic crystals.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[CH3:13])[NH2:9].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH3:13][C:12]1[CH:11]=[CH:10][C:8]([NH:9][C:16](=[O:15])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:21][CH:22]=2)=[CH:7][C:6]=1[Br:5]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: Cc1ccc(N)cc1Br
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylaluminium (2M in toluene, 15.0 ml) is added over a period of 30 min to a solution of 3-bromo-4-methyl-aniline(2.15 g, 11.5 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (2.87 g, 11.5 mmol) in toluene (20 ml) at 40° C. under an atmosphere of argon. After gas evolution ceases, the reaction mixture is stirred 30 min before being cooled to 0° C. and partitioned between cold aqueous 1N NaOH (100 ml) and toluene (100 ml). The organic layer is extracted with aqueous saturated NH4Cl (100 ml) and aqueous saturated NaCl (100 ml) The organic layer is concentrated in vacuo to give 4.69 g (97 area % by HPLC) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[C@@H:5]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1.C(Cl)Cl.Cl[C:31]([O:33][CH3:34])=[O:32]>CN(C)C1C=CN=CC=1>[CH3:1][O:2][C@@H:3]1[CH2:8][N:7]([C:31]([O:33][CH3:34])=[O:32])[C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[C@@H:5]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl(2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate (0.0233 g, 0.0000645 mol) and 4-dimethylaminopyridine (0.0118 g, 0.0000967 mol) in methylene chloride (1.00 mL, 0.0156 mol) was added methyl chloroformate (0.00648 mL, 0.0000838 mol). The reaction was stirred at rt overnight. After quenched with aq. sodium bicaronate, the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, concentrated to dry. The resulting residue was used directly in next step. MS (ESI): (M+H)+=420.2.
Reaction SMILES: C(NCCO)C.[Cl:7][CH2:8][C:9](Cl)=[O:10].[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[Cl:18][CH2:19][C:20]([N:22]([CH2:26]C)[CH2:23][CH2:24]O)=[O:21]>C(#N)C>[Cl:18][CH2:19][C:20]([N:22]([CH2:23][CH3:24])[CH2:26][CH:12]([O:15][C:9](=[O:10])[CH2:8][Cl:7])[OH:13])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CCN(CCO)C(=O)CCl
Reactant: O=C([O-])[O-]
Agent: CCNCCO
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC(O)OC(=O)CCl)C(=O)CCl
Yield: 80 %

Procedure:
N-chloroacetyl-N-ethyl-2-chloroacetoxyethanolamine was prepared in one step from N-ethylethanolamine (8.9 g., 0.1 mole) and chloroacetylchloride (97 g., 1 mole) in dry acetonitrile (100 ml) and anhydrous sodium carbonate (1.19 g., 0.11 mole) by mixing at room temperature for 48 hours. The resulting product was produced in an 80% yield following the same work-up procedure as described for N-chloroacetyl-N-ethylethanolamine in Example 1. The product shows the same behavior in the NMR spectrum in COCl3 as in N-chloroacetyl-N-ethyl-2acetoxyethanolamine due to the following equilibrium: ##STR20## Therefore, δCDCl3ppm : 4.35 (t, CH2 --O); 4.17, 4.125 ##STR21## two overlapping doublets); 3.8-3.25 (m, CH2 --N--CH2); 1.23 (q, --CH3, e.g., two overlapping triplets). m=multiplet, q=quarter, t=triplet
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (28.2 g, 231 mmol), potassium carbonate (47.9 g, 347 mmol), potassium iodide (3.84 g, 23.1 mmol) and N,N-dimethylformamide (280 mL) was added benzyl bromide (27.5 mL, 231 mmol) with stirring at room temperature, and the mixture was stirred at the same temperature for 24 hrs. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid and saturated brine, dried, and concentrated under reduced pressure to give the title compound (48 g, yield 98%) as beige crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:41])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH:33]4[CH2:35][CH2:34]4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].C1N=CN([C:55]([N:57]2[CH:61]=N[CH:59]=[CH:58]2)=[O:56])C=1.N1CC[O:65][CH2:64]C1>C1COCC1>[Si:43]([O:42][C@H:3]1[C@H:2]([NH:1][C:55]([N:57]2[CH2:58][CH2:59][O:65][CH2:64][CH2:61]2)=[O:56])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH:33]4[CH2:34][CH2:35]4)[CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[C:9]=2[Cl:41])[CH2:4]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]
Reactant: C1COCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)N5CCOCC5)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethyl silyl)oxy) piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (40 mg, 0.057 mmol) in THF (1 mL) was added to CDI (37.1 mg, 0.229 mmol) in THF (1 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. Morpholine (39.9 mg, 0.458 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. LCMS showed completion of reaction. Solvent was evaporated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 2-6% 2 N ammonia in methanol/dichloromethane). (+/−)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)morpholine-4-carboxamide (34 mg) was obtained as a white solid.
Reaction SMILES: [C:1]([O:11][CH:12]([C:14]([O:16]C)=[O:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[NH3:18]>>[C:7]([C:4]([C:1]([O:11][CH:12]([C:14]([O-:16])=[O:15])[F:13])([F:2])[F:3])([F:6])[F:5])([F:10])([F:9])[F:8].[NH4+:18]
Reactant: COC(=O)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: N
Product: O=C([O-])C(F)OC(F)(F)C(F)(F)C(F)(F)F
Product: [NH4+]

Procedure:
The ester is converted to the ammonium salt by reaction with aqueous ammonia. Methanol is removed by fractionated distillation. The resulting aqueous solution is used as an emulsifier in the polymerization of fluorinated olefins.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:40]N(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([C@H:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)([C@H](C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate (0.040 g, 0.067 mmol) from Step A above and HMPA (0.012 mL, 0.067 mmol) in anhydrous THF (1 mL) was added LDA, 2.0M in THF (0.037 mL, 0.074 mmol) at −78° C. Let it stir for 0.5 h at −78° C. Then iodomethane (0.057 mL, 0.913 mmol) was added. After stirring for 1 h, the reaction was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and the filtrate was concentrated under the reduced pressure to provide a yellow oil. This was used in the next step without further purification.
Reaction SMILES: Br[CH:2](Br)[CH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2.C=CBr.CC(C)([O-])C.[K+]>COCCOCCOCCOC.O>[C:3]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)#[CH:2]
Reactant: BrC(Br)CC12CC3CC(CC(C3)C1)C2
Agent: C=CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOCCOC
Product: C#CC12CC3CC(CC(C3)C1)C2
Temperature: 160 °C

Procedure:
A solution of 45 g (0.17 mol) of 1-bromoadamantane in 60 ml of vinyl bromide was cooled to -65° C. and 10 g of aluminum bromide was added portionwise over 2 h. The mixture was then poured on to 500 g of ice, neutralized with 10% aqueous sodium carbonate solution, and extracted with 3×100 ml of methylene chloride. The combined extracts were dried (MgSO4) and evaporated to yield 70 g of an oil containing 1-(2,2-dibromoethyl)adamantane and polyvinyl bromide (NMR). This oil was dissolved in 100 ml of triglyme, 38 g (0.34 mol) of potassium t-butoxide added, and the mixture heated at 160° C. for 3 h. The mixture was cooled, diluted with 300 ml of water and extracted with 3×100 ml of hexane. The combined hexane extracts were dried (MgSO4), and distilled to give 12 g (52% based on 1-bromoadamantane) of 1-ethynyladamantane: mp 82°-83° C.; bp 95-100 (1 mm); NMR δ1.9-2.6 ppm.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([NH2:7])=[O:6])#[N:2].[OH-:8].[Na+].[CH3:10]O>>[CH3:10][O:8][C:1](=[NH:2])[CH2:3][NH:4][C:5]([NH2:7])=[O:6]
Reactant: [OH-]
Reactant: N#CCNC(N)=O
Reactant: CO
Agent: [Na+]
Product: COC(=N)CNC(N)=O
Temperature: 30 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
100 g of cyanomethylurea is combined with a mixture of 300 ml of methanol and 5 ml of 8N sodium hydroxide solution and stirred for 3 hours at 25°30° C. The mixture is allowed to cool to 20° C., the resultant product is removed by filtration, washed with a small amount of ice-cold methanol, and dried under vacuum, thus obtaining 92.6 g of (2-methoxy-2-iminoethyl)urea (=70% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([F:36])=[C:14]([C@:16]4([CH3:35])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH:26]C(=O)C5C=CC=CC=5)=[N:17]4)[CH:15]=3)[O:8][C:4]=2[CH:3]=1.C1CCN2C(=NCCC2)CC1.CO>[NH4+].[Cl-].CCOC(C)=O>[NH2:26][C:18]1[O:19][C@H:20]([C:22]([F:25])([F:24])[F:23])[CH2:21][C@:16]([C:14]2[CH:15]=[C:10]([NH:9][C:7]3[O:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:38]=[CH:37][C:5]=4[N:6]=3)[CH:11]=[CH:12][C:13]=2[F:36])([CH3:35])[N:17]=1
Reactant: C[C@@]1(c2cc(Nc3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@]1(c2cc(Nc3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 65 °C
Reaction time: 4 h
Yield: 7.8 %

Procedure:
A mixture of N-((4S,6S)-4-(5-((6-chlorobenzo[d]oxazol-2-yl)amino)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.200 g, 0.366 mmol), DBU (0.072 mL, 0.475 mmol) and MeOH (3 mL) was stirred at 65° C. After 4 h, the mixture was diluted with saturated NH4Cl and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 0-100% in 15 min, then 100% EtOAc-hexane. The product was obtained as a white solid (67.4 mg, 91% pure). The crude was further purified by reverse phase HPLC: 10-100% in 16 min, MeCN in water with 0.1% TFA. The combined fractions were neutralized with solid Na2CO3, and extracted with DCM three times. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (12.7 mg, 8% yield). MS m/z=443 [M+H]+. Calculated for C19H15ClF4N4O2: 442.8.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Reactant: C#Cc1cnc2cccnn12
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound 3-ethynylimidazo[1,2-b]pyridazin was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 8.63-8.64 (1H, m), 8.18-8.21 (1H, m), 8.10 (1H, s), 7.32-7.35 (1H, m), 4.94 (1H, s).