Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)C(C)C)(C)C.Cl[C:29]1[O:30][C:31]2[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:32]=2[N:33]=1.C(OCC)(=O)C>CN(C=O)C>[OH:38][C:36]1[CH:35]=[CH:34][C:32]2[N:33]=[C:29]([N:8]3[CH2:9][CH2:10][CH:5]([O:4][CH2:3][C@@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:1])[CH2:6][CH2:7]3)[O:30][C:31]=2[CH:37]=1
Reactant: Oc1ccc2nc(Cl)oc2c1
Reactant: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
To a solution of tert-butyl [(1S)-1-methyl-2-(piperidin-4-yloxy)ethyl]carbamate (308 mg) and N,N-diisopropylethylamine (0.311 mL) in DMF (2 mL) was added 2-chloro-1,3-benzoxazol-6-ol (202 mg), and the mixture was stirred at room temperature for 5 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The extract was applied to silica gel chromatography (NH, ethyl acetate), and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (446 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C(Cl)(=O)OCC.N[CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24]1.C(=O)([O-])O.[Na+].C[N:42](C)C=O>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:29]([N:25]1[CH2:26][CH2:27][CH:28]([NH:42][C:13]([C:4]2[C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[CH:12]=[C:2]([Cl:1])[CH:3]=2)=[O:15])[CH2:23][CH2:24]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1COc2c(cc(Cl)cc2C(=O)O)N1
Reactant: CN(C)C=O
Reactant: NC1CCCN(Cc2ccccc2)C1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1COc2c(cc(Cl)cc2C(=O)NC2CCN(Cc3ccccc3)CC2)N1

Procedure:
A solution of 4.5 g of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 100 ml of tetrahydrofuran and 10 ml of dimethylformamide is cooled to below 0° C. and 2.5 ml of triethylamine is added under stirring thereto. Further, 2.4 g of ethyl chlorocarbonate is added and the mixture is stirred while keeping below 50° C. for an hour. To the resultant mixture is added 3.6 g of 3-amino-1benzylpiperidine and the mixture stirred for 4 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ethanol-ethyl acetate to give N-(1-benzyl-4-piperidyl) -6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxamide, melting at 203°-206° C.
Reaction SMILES: ClC1C=C(COC2C=CC(F)=CC=2)C=CN=1.FC1C=CC(CBr)=CC=1.CS([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=O)=O.C(O[C:46]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=2)[C:48](=[O:59])[CH:47]=1)C1C=CC=CC=1.[CH2:60]([N:62]([CH2:66][CH3:67])[CH2:63][CH2:64]O)[CH3:61]>>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][O:30][C:46]1[CH:51]=[CH:50][N:49]([C:52]2[CH:53]=[CH:54][C:55]([O:58][CH2:61][CH2:60][N:62]([CH2:66][CH3:67])[CH2:63][CH3:64])=[CH:56][CH:57]=2)[C:48](=[O:59])[CH:47]=1
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: CCN(CC)CCO
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Agent: Fc1ccc(CBr)cc1
Agent: Fc1ccc(OCc2ccnc(Cl)c2)cc1
Product: CCN(CC)CCOc1ccc(-n2ccc(OCc3ccccn3)cc2=O)cc1

Procedure:
Steps (1) and (2) of Example 28 were repeated except that 4-fluorobenzyl bromide used in Example 28 was replaced with 2-methanesulfonyloxymethylpyridine, and successively Example 12 was repeated except that so obtained compound was used in place of 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one in Step (3) and 2-(1-pyrrolidine)ethanol was replaced with 2-(diethylamino)ethanol, to provide the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([CH3:52])([CH3:51])[C@H:10]([NH:22][C:23]([C@H:25]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:39]([F:50])[CH:38]=1)[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])[C:11]([NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])=[O:12]>ClCCl>[CH3:51][C:9]([CH3:8])([CH3:52])[C@H:10]([NH:22][C:23]([C@H:25]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:39]([F:50])[CH:38]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:24])[C:11]([NH:13][C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])=[O:12]
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)O)C(C)(C)C)c1ccccc1
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Trifluoroacetic acid (2 mL) was added dropwise over 5 min to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-fluoro-4-phenoxyphenyl)hexanoate (876 mg, 1.41 mmol) in anhydrous dichloromethane (6 mL) under nitrogen at 20° C. The solution was stirred for 16 h and concentrated under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pressure (twice). Purification by flash chromatography (eluting with hexane:ethyl acetate:acetic acid=75:25:1) gave the title compound as a yellow gum (784 mg, 98%).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([CH2:13][C:14]#[CH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:18]([Li])[CH2:19][CH2:20]C.C(=[O:26])CC>C1COCC1>[CH2:1]([C@@H:8]1[O:9][C:10]([CH3:16])([CH3:17])[O:11][C@H:12]1[CH2:13][CH2:14][CH:15]([OH:26])[C:18]#[C:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCC=O
Reactant: [Li]CCCC
Reactant: C#CC[C@@H]1OC(C)(C)O[C@H]1CCCCCCC
Solvent: C1CCOC1
Product: CC#CC(O)CC[C@@H]1OC(C)(C)O[C@H]1CCCCCCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5S)-4-heptyl-2,2-dimethyl-5-(prop-2-ynyl)-1,3-dioxolane (19.4 mg, 0.081 mmol) in THF (0.8 mL) at −78° C. was added n-butyllithium (51 μL, 1.6 M). The mixture was stirred for 30 min. at which time propanal (excess) was added. The mixture was stirred at −78° C. for an additional 30 min. The reaction was quenched with sat'd NH4Cl (aq.) at −78° C. The title compound was isolated using a standard workup (22 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 4.30 (m, 1H), 3.81 (dt, 4 Hz, 7.6 Hz, 1H), 3.71 (m, 1H), 2.54 (dd, 1.6 Hz, 5.2 Hz, 2H), 1.39 (s, 6H), 1.28 (m, 12H), 0.99 (t, 7.6 Hz, 3H), 0.87 (t, 6.4 Hz, 3H). LRMS (APCI+) found 279.7, [M−H2O]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([CH2:22][CH:23]2[CH2:28][CH:27]([OH:29])[CH2:26][CH2:25][CH:24]2[C:30](=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[O:12][C:11]1([CH3:38])[CH3:37])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:39]I>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([CH2:22][CH:23]2[CH2:28][CH:27]([O:29][CH3:39])[CH2:26][CH2:25][CH:24]2[C:30](=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[O:12][C:11]1([CH3:38])[CH3:37])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)(C)NC(=O)C1CCC(O)CC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC(C(=O)NC(C)(C)C)C(CC2OC(C)(C)N(C(=O)OC(C)(C)C)C2Cc2ccccc2)C1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Sodium hydride (60% w/w in mineral oil, 20 mg, 0.52 mmol) was added to a solution of 4-benzyl-5-(2-tert-butylcarbamoyl-5-hydroxy-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (200 mg, 0.40 mmol) in dry N,N-dimethylformamid (4 ml) stirred at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. until gas evolution had ceased. Methyl iodide (40 μl, 0.6 mmol) was then added, and the solution was allowed to warm to room temperature and stirred for 20 hours. After removal of the volatiles in vacuo, the crude product was dissolved in ethyl acetate, washed twice with water, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel provided 4-benzyl-5-(2-tert-butylcarbamoyl-5-methoxy-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (125 mg, 96%).
Reaction SMILES: [C:1]([C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][O:24][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:23]1[O:24][C:17]2[CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:26][CH:25]=3)[CH2:21][CH2:20][CH2:19][C:18]=2[CH:22]=1)[CH3:29]
Reactant: C=O
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCCc3ccoc3C2)cc1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CCC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.237 g (0.686 mmol) of 7-(4-benzoylbenzoyl)-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine in 20 ml of acetic acid, 74 mg (0.82 mmol) of 50% aqueous dimethylamine and 67 mg (0.82 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]([NH2:11])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N([CH2:17][CH3:18])CC)C.[C:19]1(C)[CH:24]=C[C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[C:17]1([CH3:18])[C:22]([S:25]([NH:11][C:2]([CH3:1])([CH3:10])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=[CH:19][CH:24]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(N)Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(C)(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
To a nitrogen-blanketed solution of 1,1-dimethyl-2-phenyl-ethylamine (3.56 g, 0.019 mol), methylene chloride (CH2Cl2, 20 mL) and triethylamine (Et3N, 8.01 mL, 0.058 mol) was added para-toluenesulfonyl chloride (TsCl, 4.39 g, 0.023 mol). The mixture was stirred at room temperature for 12 hours while monitoring by gas chromatography. The reaction mixture was partitioned between methylene chloride (100 mL) and water (100 mL) and the organic layer was separated and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated to give 5.73 g of N-toluenesulfonyl-1,1-dimethyl-2-phenyl-ethylamine (yield=99%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:14])(O)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.CN(C)[CH:21]=[O:22]>>[CH3:17][O:12][CH2:11][C:10]([O:22][CH3:21])([CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CO)COCc1ccccc1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCC(C)(COCc1ccccc1)OC
Reaction time: 4 h

Procedure:
1-(Benzyloxymethyl)-1-methylethane-1,2-diol (10 g) and sodium hydride (1.2 g) were stirred together in dimethyl formamide (50 ml) for 12 h; the reaction mixture was then treated with methyl iodide (7.1g) and again stirred for 4 h. The reaction product was then stripped at 100°/1 mm and the residue purified by chromatography on silica gel eluted with 9/1 methylene chloride/ether to give a small forerun of 1,2-dimethoxy-2-methyl-3-benzyloxypropane and then 11 g 1-methoxy-3-benzyloxy-2-methylpropan-2-ol as a colourless oil. The structure was confirmed by n.m.r. techniques.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].C(OC([N:32]1[C:40]2[C:35](=[CH:36][C:37]([P:41]([O:45]C)([O:43][CH3:44])=[O:42])=[CH:38][CH:39]=2)[C:34](I)=[N:33]1)=O)(C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH3:44][O:43][P:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][N:33]=[C:34]2[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:42])[OH:45]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: COP(=O)(OC)c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(O)c1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 43.7 %

Procedure:
82.9 mg (0.25 eq; 0.072 mmol) of tetrakis(triphenylphosphine)palladium(0), 150.1 mg (2 eq; 0.575 mmol) of 1-boc-indole-2-boronic acid, 5 ml of dimethylformamide and 250 μl of saturated sodium bicarbonate solution are added to 130 mg (1 eq; 0.287 mmol) of 5-(dimethoxyphosphoryl)-3-iodo-indazole-1-carboxylic acid tert-butyl ester. The medium is stirred at 130° C. for 5 hours. The reaction medium is filtered through paper and the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 41 mg of [3-(1H-indol-2-yl)-1H-indazol-5-yl]-phosphonic acid monomethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[CH3:10][S-:11].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:11][CH3:10])[N:3]=1
Reactant: C[S-]
Reactant: BrCc1cccc(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCc1cccc(Br)n1
Temperature: 80 °C

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.20 g, 0.80 mmol) and sodium thiomethoxide (0.072 g, 1.04 mmol) were taken up in DMF (12.1 mL) heated at 80° C. for 3 hours. The reaction was then cooled to ambient temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography to yield the title compound. 1H NMR (600 MHz, CDCl3): 7.53 (t, J=9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 3.77 (s, 2H), 2.08 (2, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:50][S:51]([O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[C:5]([C:16]#[N:17])[CH:4]=[C:3]([NH:18][C:19]3[N:24]=[C:23]([N:25]([CH:35]4[CH2:37][CH2:36]4)[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[C:22]4=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]4[N:20]=3)[C:2]=2[Cl:1])[CH2:9]1)(=[O:53])=[O:52]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(COS(C)(=O)=O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask charged with (+/−)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.05 g, 0.085 mmol) in THF (0.427 ml) was added triethylamine (0.036 ml, 0.256 mmol) and methanesulfonyl chloride (9.97 μl, 0.128 mmol). The reaction mixture was stirred at room temperature 2 h. The reaction mixture was poured into a separatory funnel containing 1:1 saturated aqueous sodium bicarbonate: ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. (4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl methanesulfonate was isolated as a pale yellow solid and used as is for further chemistry.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH2:16])[C:9]=2[CH3:17])[CH2:5][C:4](=[O:18])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21].N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30].O>ClCCl>[OH:18][C:4]1[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH:16][C:29](=[O:31])[CH3:30])[C:9]=2[CH3:17])[CH2:7][C:2](=[O:1])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21]
Reactant: CC(=O)Cl
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NC(C)=O)c2C)CC1=O
Yield: 33.9 %

Procedure:
A solution of 3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (2.6 g; 8.6 mmole) and pyridine (0.7 g; 9 mmole) in dichloromethane (100 ml) was treated with acetyl chloride (0.69 g; 9 mmole) at 20° C. with stirring. After 1.5 hours the mixture was poured into water (100 ml) and shaken. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure using a rotary evaporator. The product was purified by chromatograpy over silica gel (eluent 1% methanol in dichloromethane) to give 3-hydroxy-5-(3-acetamido-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (1.0 g, 34%) as a pale orange semi-crystalline solid. Proton magnetic resonance spectrum (CDCl3, δ in ppm): 1.20 (3H, t); 2.18 (3H, s); 2.20 (3H, s); 2.27 (3H, s); 2.35 (3H, s); 2.4-4.0 (7H, m); 6.6 (1H, bs); 6.88 (1H, s); 18.20 (1H, s).
Reaction SMILES: O.[N+:2]([CH:5]([CH:8]=O)[CH:6]=O)([O-:4])=[O:3].[Na].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.[CH:21]([OH:23])=O>CO.O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]/[N:18]=[CH:8]/[CH:5]([N+:2]([O-:4])=[O:3])/[CH:6]=[N:18]/[CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:23][CH3:21])=[CH:14][CH:15]=2)=[CH:15][CH:14]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: O=CO
Reactant: COc1ccc(CN)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccc(C/N=C/C(/C=N/Cc2ccc(OC)cc2)[N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 37 %

Procedure:
A yellow-orange suspension of sodium nitromalonaldehyde monohydrate (15.7 mg, 0.10 mmol) in methanol (275 uL) and water (25 uL) was added dropwise over a 2 min period to a solution of 4-methoxybenzylamine in methanol (165 uL), water (15 uL) and 96% formic acid (0.83 uL, 0.022 mmol) and was stirred at room-temperature for 24 h. It was noted that during the NMA addition a precipitate started to crystallize out, and was analyzed and found to be the crude title compound (I2). Filtration gave a pale-yellow powder (14.5 mg, 41% crude yield) that was recrystallized from a minimum volume of absolute ethanol (˜0.75 mL) yielding 13 mg (37%) of the title compound as pale-yellow, microcrystalline flakes: mp 131.5-132° C.; HRMS calcd for C19H22N3O4 (M+H+) 356.1610, obsd 356.15571; 1H NMR (300 MHz, DMSO-d6) δ 3.737 (s, 6H), 4.621 (s, 4H), 6.891, 6.885, 6.869, 6.862 (dd, 4H), 7.196-7.167 (d, 4H), 8.840 (s, 2H), ˜11.7 (br s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 145.704, 135.410, 135.380, 128.787, 128.382, 128.199, 127.879, 127.230, 120.561, 64.383, 57.309, 52.166; Anal. Calcd for C19H21N3O4 (355.39): C, 64.21; H, 5.96; N, 11.82. Found: C, 64.04; H, 5.96; N, 11.86.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:14]1=2>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]2[C:13](=[CH:12][C:6]3[CH:7]=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[C:14]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:15]=3[CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=CBr
Reactant: OB(O)c1cccc(O)c1
Product: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=Cc1cccc(O)c1
Yield: 33.5 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-hydroxyphenyl boronic acid (304 mg, 2.2 mmol) with 5-bromomethylene-2,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (690 mg, 2 mmol) to give 990 mg crude product. Purify the crude product using column chromatography eluting with 8% EtOAc/hexane to 25% EtOAc/hexane to give 240 mg (33%) product as a colorless oil. MS (ES) 357 (M−1). HPLC shows 99% purity at t=3.33 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:10][OH:11])=[CH:5][C:6]=1[I:9])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1c(I)cc(CO)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
C2 (7.14 g, 25.0 mmol) is dissolved in DMF (50 mL) in a dry flask under N2, sodium hydride (60% dispersion in mineral oil) (1.0 g, 25.0 mmol) is added, and the reaction is stirred for 1 h at rt. Allyl bromide (2.38 mL, 27.5 mmol) is added, and the reaction mixture is stirred 48 h at rt. The mixture is diluted with EtOAc (50 mL) and washed 4×25 mL of a 50% saturated solution of 1:1 NaCl/NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to a white solid. The solid is washed with hexane and dried to afford 3-(allyloxy)-2-chloro-6-(hydroxymethyl)-4-iodopyridine (C50) as a white solid (68% yield). MS (EI) for C9H9ClINO2, m/z: 325 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][CH:13]([O:22][CH2:23][CH3:24])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:11]>N1CCCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:15]([C:14]([CH:13]([O:12][CH2:10][CH3:11])[O:22][CH2:23][CH3:24])=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)C(OCC)OCC
Yield: 106.4 %

Procedure:
A solution of 2-chlorobenzaldehyde (1.0543 g), ethyl 4,4-diethoxyacetoacetate (1.6477 g) and piperidine (1 to 2 drop(s)) in benzene (30 ml) was refluxed under azeotropic dehydration for 4.5 hours. After cooling, the resultant solution was washed with water and dried. The solvent was removed from the solution to give orange oil (2.7196 g) of ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-amino-4,4-diethoxycrotonate (1.6580 g) was heated with stirring at about 100° C. for 1.5 hours and about 120° C. for 8 hours. After cooling, the reaction mixture was dissolved in ethyl acetate. The solution was washed with water and dried, and then the solvent was removed from the solution to give orange oil (4.21 g) of diethyl 2,6-bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. The product was purified by a column chromatography on silica gel with an eluent (benzene:ethyl acetate=10:1) to give pure product.