Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1.CS(O[CH2:18][C:19]1[N:27]=[C:26]2[C:22]([N:23]=[CH:24][N:25]2[C@H:28]2[C@H:32]([OH:33])[C@H:31]([OH:34])[C@@H:30]([CH2:35][O:36][CH3:37])[O:29]2)=[C:21]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:20]=1)(=O)=O.C(N(C(C)C)C(C)C)C>C(O)C.ClCCl>[OH:33][C@@H:32]1[C@H:31]([OH:34])[C@@H:30]([CH2:35][O:36][CH3:37])[O:29][C@H:28]1[N:25]1[CH:24]=[N:23][C:22]2[C:26]1=[N:27][C:19]([CH2:18][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1)=[N:20][C:21]=2[NH:38][CH2:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CS(=O)(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN[C@H]4CC[C@H](NS(C)(=O)=O)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(trans-4-Aminocyclohexyl)methanesulfonamide (183 mg, 0.8 mmol) (preparation 33) was added to a stirred solution of {9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (230 mg, 0.4 mmol) (preparation 25) and N-ethyl-N-isopropyl-2-propanamine (210 mg, 1.6 mmol) in ethanol (3 ml) and dichloromethane (12 ml). The reaction mixture was stirred for 48 hr at room temperature. The solvent was then removed under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (98:2:0.3) increasing in polarity to (90:10:1) to give the title compound (50 mg) as a foam. MS: 667 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[N:26]1([C:32]2[S:33][C:34]([C:37](O)=[O:38])=[CH:35][N:36]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:37]([C:34]1[S:33][C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:36][CH:35]=1)=[O:38])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(O)c1cnc(N2CCOCC2)s1
Product: CN(C)C(=O)c1c(CNC(=O)c2cnc(N3CCOCC3)s2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-{[(2-morpholin-4-yl-thiazole-5-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 2-morpholin-4-yl-thiazole-5-carboxylic acid. MS calcd. for C27H26ClN5O4S [(M+H)+] 552.1, obsd. 552.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:31])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:46])C=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:31])[CH2:21][S:22]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:46])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(SCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)CC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(4-methoxyphenylthio)ethyl]pyrrolidine (1.51 g) was subjected to oxidation as in Example 2-A) in dichloromethane using 1.1 equivalent of m-chloroperbenzoic acid to give 984 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]([NH2:23])[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1.[O:24]([CH2:28][CH:29]=O)[CH2:25][CH:26]=O.O.[BH3-]C#N.[Na+].Cl>CC#N>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]([N:23]2[CH2:29][CH2:28][O:24][CH2:25][CH2:26]2)[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C(N)C(c2cccnc2)c2cccnc2)n1
Reactant: O=CCOCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(C(C(c2cccnc2)c2cccnc2)N2CCOCC2)n1

Procedure:
To a solution of 1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethanamine (75 mg, 0.25 mmole) in CH3CN (1 mL) was added a solution of 2,2′-oxydiacetaldehyde in H2O (1.47 mL, 0.5 M, 0.73 mmole). After 10 minutes NaBH3CN (92 mg, 1.47 mmole) was added. After 2 hr 1N HCl (2 mL) was added.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]3[CH3:23])[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:29]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:29])=[O:15])[CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]3[CH3:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1COCCN1c1cc(C(=O)O)nc(-c2ccc(N)cc2)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-(4-Aminophenyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylic acid (1.15 g) was dissolved in methanol (15 mL), sulfuric acid (0.01 mL) was added and the reaction was heated at 80° C. for 24 h. A small quantity of activated molecular sieve 4A was added to the reaction and stirred for 2 h. The reaction was filtered, vacuumed to dryness then suspended in ethyl acetate (250 mL) and washed once with a saturated solution of sodium bicarbonate (250 mL). The organic layer was filtered, dried over magnesium sulphate and vacuumed to dryness to give the desired material as a brown solid (405 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]=2[CH:18]=1)=[O:7])C>>[CH3:16][C:14]1([CH3:17])[CH2:13][C:12]2[CH:18]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[CH:10][C:11]=2[O:15]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)Cc2cc(C(=O)O)ccc2O1
Temperature: 75 °C

Procedure:
An aqueous solution (10 mL) of sodium hydroxide (0.78 g, 0.0195 mol) is added to an ethanolic solution (30 mL) of 2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid ethyl ester (3.9 g, 0.018 mol). The reaction mixture is heated at 75° C. for four and an half hours. Ethanol is removed under reduced pressure. Demineralized water is added to the residue and pH is brought to ˜3 with 1 N HCl. Solid thus obtained is filtered, washed with demineralized water and dried under reduced pressure to give 2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
Triethylamine (4.2 ml) was added to a stirred solution of 2,4-dichloronitrobenzene (1.9 g) and 1-t-butoxycarbonyl-piperazine (2.2 g) in dimethylsulfoxide (18 ml) under N2. The resulting solution was stirred at 70° C. for 48 hours then cooled to room temperature. Water was added and the mixture extracted three times with ethyl acetate; the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (cyclohexane:ethyl acetate 8:2) to afford 4-(5-chloro-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.6 g) as a foam. 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.9 (br s, 4H), 3.5 (br s, 4H), 6.9 (d, J=10 Hz, 1H), 7.0 (s, 1H), 7.7 (d, J=10 Hz, 1H); MS (ES+) 242/244 (M+H+—CO2-isobutene), 286/288 (M+H+-isobutene).
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2cc(-c3ccc(F)nc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc(F)nc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Methyl 4-({cyclohexyl[5-(6-fluoropyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoate (1.7 g) was dissolved in tetrahydrofuran (10 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give the title compound (1.2 g, 74%) as an amorphous compound.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].CC1C=C(N([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)C2C=CC(C)=C(C)C=2)C=CC=1C>C1(C)C=CC=CC=1>[CH2:1]([O:3][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[CH2:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:28]=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Into a three-necked flask, 40 ml of toluene, 6.0 g (37 mmol) of triethoxysilane and 0.34 mmol of platinum (II) dichloro(h-cycloocta-1,5-diene) were placed, and 20 ml of a toluene solution containing 9.9 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was added dropwise with stirring at room temperature. After the addition was completed, the mixture was stirred at 70° C. for 3 hours, and thereafter the solvent was removed under reduced pressure to obtain oily pale yellow 4-[N,N-bis(3,4-dimethylphenyl)amino]-[2-(triethoxysilyl)ethylbenzene in an amount of 14.0 g (yield: 94.2%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-])=O)[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([OH:26])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(C)C.[Pd]>[NH2:27][C:17]1[C:18]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([OH:26])[CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@@H](O)C1
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To the reaction mixture from the above step containing (1R,3R)-3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino) cyclohexanol (8.65 mmol) in isopropyl alcohol (30 mL) was added 10% Palladium on activated carbon (718 mg). The reaction mixture was then capped with a 3 way glass valve with a hydrogen gas balloon. The flask was opened to vacuum for two minutes, followed by opening to hydrogen. This purge/flush cycle was repeated 3 times before stirring under a hydrogen atmosphere at room temperature for 2 days. LC/MS showed that the reaction went to completion. The reaction mixture was then filtered through celite 545 and concentrated to give a black foamy solid, which was used as is for the next step. LCMS (Method M, ESI): RT=1.44 min, m+H=386.8.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])=[CH:20][CH:21]=1
Reactant: CN(C)c1ccc(CNc2ccc(Br)cc2)cc1
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Product: CN(C)c1ccc(CN(C(=O)C2CCCc3ccc(F)cc32)c2ccc(Br)cc2)cc1
Yield: 25.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amine (0.64 g) as starting materials, N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(OC)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(CNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 90.4 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylate (0.067 g, 0.12 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodium hydroxide (0.26 ml, 0.26 mmol). The reaction was stirred for 16 hours, and then concentrated, diluted with water, and acidified with 1M hydrochloric acid. The mixture was extracted twice with EtOAc, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 56 mg of the title compound (88% yield).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH2:32][C:33](N(OC)C)=[O:34])=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH2:32][C:33]([C:23]2[CH:22]=[CH:21][N:20]=[N:19][C:18]=2[O:17][CH3:16])=[O:34])=[CH:29][CH:30]=1
Reactant: COc1cccnn1
Reactant: CON(C)C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nnccc1C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 37.4 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (1.28 g, 9.09 mmol) in THF (60 mL) was added n-butyllithium (1.6 M in hexane 6.7 mL, 9.1 mmol) at −30° C., then the solution was stirred at 0° C. for 45 min. After cooling to −70° C. a solution of 3-methoxypyridazine (1.00 g, 9.09 mmol) in THF (6 mL) was added dropwise, then a solution of (S)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 1, step 5; 823 mg, 2.27 mmol) in THF (6 mL) was added, maintaining the temperature as close as possible to −70° C. The mixture was stirred for 30 min. Sat. aq. ammonium chloride solution (30 mL) was added. The reaction mixture was allowed to reach room temperature and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) afforded the title compound (349 mg, 37%). Light red solid, MS: 411.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([N:15]([CH2:24][O:25][CH3:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:26][O:25][CH2:24][N:15]([C:13]1[CH:14]=[C:9]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:10]=[CH:11][N:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23]
Reactant: COCN(c1cc(Cl)ncn1)c1cccc(F)c1F
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(COC)c2cccc(F)c2F)ncn1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.03 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.04 g of 2-butyn-1-ol were slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.16 g of 4-chloro-6-(N-methoxymethyl-N-(2,3-difluorophenyl)amino)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(N-methoxymethyl-N-(2,3-difluorophenyl)amino)-6-(2-butynyloxy)pyrimidine (the present compound (79)).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.BrC[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>C1COCC1>[CH:19]1([CH2:18][C:9]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]2)[CH2:21][CH2:20]1
Reactant: BrCCC1CC1
Reactant: O=C(O)C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C1(CC2CC2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.5 %

Procedure:
To a solution of LDA (100 ml, 2.0 M THF solution) in THF (100 ml) was added dropwise over a period of 20 minutes at 0° C., a solution of cyclobutane carboxylic acid (10 g, 0.1 mol) in THF (15 ml). The resulting mixture was stirred at RT for 2 h then bromoethylcyclopropane (15 g, 0.11 mol) was added dropwise and the mixture was stirred at RT. overnight. To the reaction mixture was added 2N HCl and the mixture was extracted with EtOAc. The organic layer was washed with water and brine to afford the title compound as light yellow oil (19.2 g), which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)[CH:17]=[CH:18][CH:19]=3)[N:12]=2)[N:7]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:6]=1)=[O:4].[CH3:47][S:48]([CH:51]1[CH2:55][CH2:54][NH:53][CH2:52]1)(=[O:50])=[O:49].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:47][S:48]([CH:51]1[CH2:55][CH2:54][N:53]([C:16]2[CH:15]=[C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:45])[CH3:46])=[CH:6][N:7]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:8]4=[N:9][CH:10]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:52]1)(=[O:50])=[O:49]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c3)nc12
Reactant: CS(=O)(=O)C1CCNC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CCC(S(C)(=O)=O)C4)c3)nc12
Temperature: 115 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonic acid 3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl ester (120 mg, 0.17 mmol), 3-methanesulfonyl-pyrrolidine (˜40 mg, 0.26 mmol), Pd2(dba)3 (8 mg, 0.009 mmol), Xantphos (11 mg, 0.02 mmol), and K3PO4 (72 mg, 0.34 mmol) in toluene (1.5 mL) was stirred in a sealed tube under argon at 115° C. overnight. The resulting mixture was partitioned between ethyl acetate and water. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography using 4 g of silica gel and 20-100% EtOAc in hexanes as eluant to afford 0.08 g of impure 1-[2-[3-(3-methanesulfonyl-pyrrolidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one. M+Na 579.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[CH:13][O:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[CH2:1]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[C:13]([B:22]([OH:27])[OH:23])[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc3ccoc3c2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2ccc(Cc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a purple mixture of benzofuran-6-ol (1.85 g, 13.8 mmol) and N,N-diisopropylethylamine 99% (7.21 mL, 41.4 mmol) in 50 mL DCM was added 1,1,1-trifluoro-n-phenyl-n-((trifluoromethyl)sulfonyl)methanesulfonamide (4.93 g, 13.8 mmol). The reaction became light blue. After 2 h, the reaction was light yellow. The reaction was quenched with saturated aq. sodium bicarbonate, and the aqueous layer was extracted with DCM. The combined organics were dried over anhyd sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, 0-15% EtOAc/hexanes, to give benzofuran-6-yl trifluoromethanesulfonate as a semi-solid. A portion of the unpurified material was carried on as follows. A mixture of 9-benzyl-9-bora-bicyclo[3.3.1]nonane 0.5M in THF (23 mL, 11 mmol), benzofuran-6-yl trifluoromethanesulfonate (1.50 g, 5.6 mmol), potassium phosphate (3.6 g, 17 mmol), benzofuran-6-yl trifluoromethanesulfonate (1.50 g, 5.6 mmol), S-Phos (0.19 g, 0.45 mmol), Pd(OAc)2 (0.051 g, 0.23 mmol) was flushed with argon, sealed, and heated to 60° C. overnight. The green/gray reaction was cooled and filtered through celite rinsing with Et2O. The filtrate was concentrated and adsorbed onto 15 g silica gel and dried. The material was purified by silica gel chromatography, ISCO, 80 g, 0-10% EtOAc/hexanes to give 6-benzylbenzofuran. A portion of this material was processed as follows. To a solution of 6-benzylbenzofuran (0.663 g, 3.18 mmol) in 30 mL THF at −78° C. was added 1-butyllithium 2.5 M in hexanes (1.53 mL, 3.82 mmol) slowly dropwise. The reaction was allowed to stir for 25 min, at which point triisopropyl borate (1.08 mL, 4.68 mmol) was added slowly dropwise. After 0.5 h, the bath was removed and the reaction was allowed to warm to ambient temperature. After 10 min, 50 mL 2N HCl was added. The mixture was diluted with MTBE, and the organics were washed with brine, dried over anhyd. MgSO4, filtered, and concentrated in vacuo to give an oil. The oil was treated with hexanes to give a solid, and the material was filtered and rinsed with hexanes and dried in vacuo to give 6-benzylbenzofuran-2-ylboronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (s, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.24-7.33 (m, 4H), 7.15-7.22 (m, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.06 (s, 2H).