Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.FC(F)(F)C(O)=O.[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:47])[C@@H:35]([NH2:46])[CH2:36][CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:47])[C@@H:35]([NH:46][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:36][CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 1.7 g of 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 15 ml of DMF, 566 mg of NEM, 753 mg of HOBT and 943 mg of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was precipitated from a mixture of n-heptane and ethyl acetate. The precipitated product was collected by filtration and dried under reduced pressure. The isolated product was pure enough for the next reaction step. Yield: 1.8 g.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[CH2:23]([NH2:28])[C:24]#[C:25][CH2:26][CH3:27]>O1CCCC1>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:28][CH2:23][C:24]#[C:25][CH2:26][CH3:27])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Reactant: CCC#CCN
Solvent: C1CCOC1
Product: CCC#CCNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1

Procedure:
A mixture of 10.0 g. of 1,3-dihydro-7-(trifluoromethyl)-5-phenyl-2H-1,4-benzodiazepine-2-thione (V), 10.0 g. of 2-pentynylamine, and 150 ml. of dry tetrahydrofuran is stirred under nitrogen at ambient temperature for about 5 hours and then concentrated in vacuo. The residue thus obtained is recrystallized from methanol to give 7-trifluoromethyl-5-phenyl-2-(2-pentynylamino)-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:2].[OH-:31].[K+]>C(O)CCC>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccccc4)cc23)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 85 °C
Yield: 59.9 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(7-cyano-5-phenyl-1H-indazol-3-yl)-1-piperidine-carboxylate (Intermediate 4) (1.1 g, 2.7 mmols), and potassium hydroxide (1.53 g, 27.3 mmols) in n-butanol (100 mL) was heated at 85° C. for 2-3 days then at reflux overnight. The solution was cooled and the solvent removed in vacuo. The resulting residue was purified via silica gel chromatography eluting with 50% ethyl acetate/pentane, 100% ethyl acetate, and 30% methanol/ethyl acetate to give 0.68 g of a yellow solid. LC/MS M+H 421
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:12]([OH:14])=[O:13])=C1.[Na][Na]>>[C:4]1([CH2:3][CH2:10][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)(=[O:17])=[O:18])[C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: [Na][Na]
Product: O=C(O)[C@H](CCc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
(R)-3-(1H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid, disodium salt, monohydrate;
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[S:8][C:9]([C:13]2[CH:14]=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:16]([Cl:19])=[N:17][CH:18]=2)=[C:10]([CH3:12])[N:11]=1>C1COCC1>[Cl:19][C:16]1[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:14][C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])=[CH:18][N:17]=1
Reactant: CCN=C=O
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(C)(=O)=O)c2)s1
Temperature: 125 °C

Procedure:
Ethyl isocyanate (0.036 mL) was added to a stirred solution of N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]methanesulfonamide (48 mg) in THF (0.5 mL) and the mixture was placed in a sealed glass reaction vessel and heated to 125° C. in a microwave reactor for 1 hour. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using a solvent gradient of 0% to 6% methanol in dichloromethane as eluent. The material so obtained was purified further by preparative HPLC on reversed-phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (16 mg); 1H NMR Spectrum: (DMSOd6) 1.07 (t, 3H), 2.31 (s, 3H), 3.1, (s, 3H), 3.10-3.20 (m, 2H), 6.54 (br s, 11H), 7.82 (d, 1H), 8.24 (s, 1H), 9.84 (s, 1H), 10.53 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[CH:23]=[C:8]2[C:9]([C:15]3[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[N:7]2[N:6]=1)=[O:4].Cl>[N+]([O-])([O-])=O.[Ag+]>[CH3:14][O:13][C:12]1[N:7]2[N:6]=[C:5]([C:3]([OH:1])=[O:4])[CH:23]=[C:8]2[C:9]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:10][CH:11]=1
Reactant: [OH-]
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=O)nn12
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(=O)O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
An aqueous solution (1 mL) of sodium hydroxide (41.9 mg) was added to an aqueous solution (3 mL) of silver nitrate (89.0 mg). To this mixture, the compound of Example 237 (60.0 mg) was added and the resulting mixture was stirred at room temperature for 1 hour. Subsequently, 5% hydrochloric acid was added to adjust the pH to 3. The insoluble material was separated by filtration and washed with a 7:1 mixture of chloroform and methanol. The filtrate and wash were combined. Sodium chloride was then added and the mixture was extracted with a 7:1 mixture of chloroform and methanol. The extract was dried over an hydrous magnesium sulfate and the solvent was evaporated. Methanol was added to the residue and the insoluble material was removed by filtration. The solvent of the filtrate was evaporated to afford the title compound as a pale yellow powder (46.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:21]2[C:14]3=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]3[CH2:18][CH2:19][CH2:20]2)=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=S1(=O)CCN2CCCC(c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4cccc(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A mixture of 3-chlorophenylboronic acid (167 mg), 4-(2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (100 mg), diacetoxycopper (130 mg), triethylamine (0.248 mL), and powdered 4A MS (1.00 g) in MeCN (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc), and then recrystallized from EtOAc-IPE to give the title compound (37.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1/[CH:20]=[C:9](\[CH3:10])/[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CC(=O)CCc1ccccc1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1/C=C(\C)CCc1ccccc1
Yield: 69.5 %

Procedure:
The procedure of Example 41 was repeated with the exception that 3.5 g of benzyl acetone in place of cinnamic aldehyde and 2.26 g of 3-ethyl-4-methylpyridine were used in Example 41, to obtain 3.26 g (yield: 59.8%) of (E)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl -1-butene (hereinafter referred to as compound 55) and o.95 g (yield: 17.4%) of (Z)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl-1-butene (hereinafter referred to as compound 56). The analytical results are shown below.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:31][CH:30]([CH2:32][C:33](OC)=[O:34])[CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH:30]5[CH2:31][O:28][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: COC(=O)CC1COC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 85%), MS (ISP) m/z=429.3 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and methyl 2-oxetan-3-yl-acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][C:28]([SH:31])([CH3:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:31][C:28]([CH3:30])([CH3:29])[CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: CC(C)(C)S
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 4, using the following starting materials: [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester and 2-methyl-2-propanethiol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]3[N:21]([C:31]4[N:32]=[CH:33][N:34]=[C:35]([NH2:38])[C:36]=4[N:37]=3)[C@@H:22]3[O:30][C@H:27]([CH2:28][OH:29])[C@@H:25]([OH:26])[C@H:23]3[OH:24])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(OC([NH:49][C:50](N1C=CC=N1)=[NH:51])=O)C1C=CC=CC=1>O1CCCC1.[Pd].CO>[NH:1]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]3[N:21]([C:31]4[N:32]=[CH:33][N:34]=[C:35]([NH2:38])[C:36]=4[N:37]=3)[C@@H:22]3[O:30][C@H:27]([CH2:28][OH:29])[C@@H:25]([OH:26])[C@H:23]3[OH:24])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[C:50]([NH2:51])=[NH:49]
Reactant: NCCCOc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)NCCCOc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 23.1 %

Procedure:
8-[3′-(3-Aminopropoxy)biphenyl-4-ylmethylamino]-adenosine (0.2 g) was suspended in tetrahydrofuran (2 mL), N-benzyloxycarbonyl-1H-pyrazole-1-carboxamidine (0.47 g) was added, and the resulting mixture was stirred at 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=8/1-6/1). A mixture of the compound obtained and 10% palladium on carbon (43.8 wt % H2O, 0.05 g) in methanol (2 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure to give the title compound (0.05 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11](Cl)(=[O:13])=[O:12].C1OC(C2C=CSC=2)OC1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C(N(CC)CC)C>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1sccc1C1OCCO1
Agent: c1cc(C2OCCO2)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NS(=O)(=O)c2sccc2C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride (11.16 g), prepared from thiophene-3-carboxaldehyde ethylene acetal as described in Example 6, Step A, in THF (100 mL) at 0° C. was combined with p-anisidine (7.87 g, 63.9 mmol) and triethylamine (4.04 g, 40 mmol). After stirring for 4 hr at ambient temperature, the mixture was evaporated to a residue which was extracted with ethyl acetate (2×150 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 40% ethyl acetate/hexane) to give an oil (10.21 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[N:17]=3)[N:14]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[N:17]=3)[N:14]=2)=[CH:3][C:2]=1[NH:1][S:30]([C:24]1[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=1[Cl:22])(=[O:31])=[O:32]
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(N)c3)ccc2n1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4c(C)cccc4Cl)c3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
To a 50 mL, round-bottomed flask was added N-(6-(5-amino-6-chloropyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide from Step 2 (30 mg, 99 μmol), 2-chloro-6-methylbenzenesulfonyl chloride (149 μl, 661 μmol, Alfa Aesar, Ward Hill, Mass.), and pyridine (5 mL). The reaction mixture was stirred at 25° C. for 15 h and concentrated in high vacuum. Purification by silica gel chromatography (5 to 20% MeOH/CH2Cl2 provided N-(6-(6-chloro-5-(2-chloro-6-methylphenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (20 mg, 41% yield) as an off-white solid. MS (ESI positive ion) m/z: 491 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.13 (s, 3H), 2.59 (s, 3H), 7.37 (d, J=7.03 Hz, 1H), 7.50 (q, J=7.53 Hz, 2H), 7.83 (d, J=9.54 Hz, 1H), 8.13 (d, J=9.03 Hz, 1H), 8.31 (s, 1H), 8.38 (s, 1H), 8.91 (s, 1H), 10.71 (s, 1H), 10.99 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH:3]([NH:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][OH:5].[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:20][C:19]([Si:16]([CH3:18])([CH3:17])[O:5][CH2:4][CH:3]([NH:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([OH:1])[CH3:15])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCC(=O)NC(CO)C(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.5 %

Procedure:
A mixture of 11c, (1.945 g) of t-butyldimethylsilyl chloride, (1.4165 g) of triethylamine (951 mg, 1.31 mL), and 4-dimethylaminopyridine (42.76 mg) in 13 mL of methylene chloride is stirred under argon at room temperature for 18 h. The reaction mixture is diluted with methylene chloride and water added. The organic layer is separated, washed with water, dried and evaporated to give 3.25 g of a residual oil which is purified by chromatography by elution with 1:5 ethyl acetate/hexane to give 2.30 g of the desired product as an oil. NMR δ 0.08 (d, 6 H), 0.89 (t, 3 H), 0.90 (s, 9 H), 1.16 (d, 3 H), 1.65 (m, 2 H), 2.24 (t, 2 H), 3.47 (s, 1 H), 3.84 (m, 1 H), 3.85 (s, 2 H), 4.28 (q, 1 H), 6.13 (brd, 1 H); MS (FAB) m/z=332 (M+H calc'd for C17H38NO3Si 332).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
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: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Yield: 69.4 %

Procedure:
To a stirred solution of 4-tert-butyl-bromobenzene (21.3 g, 0.0999 mol) in THF (30 mL) at −78° C. under nitrogen was added dropwise a 2.1 M solution of n-butyl lithium in hexanes (45 mL, 0.095 mol), and the mixture was stirred for 1.5 hours. To the mixture was added dropwise neat trimethylborate (10.2 mL, 0.090 mol), and the mixture was allowed to slowly warm to room temperature. The mixture was stirred overnight, then quenched by dropwise addition of 1.0 M aqueous hydrochloric acid. Brine was added, and the organic layer was dried (Na2SO4) and rotary evaporated. The residue was crystallized from n-heptane to give 4.65 g of crude 4-tert-butyl-phenyl-boronic acid as white needles. This material was used directly in the next reaction without further characterization. Thus, in a manner similar to Example 12, Step (b), 4-tert-butyl-phenyl-boronic acid (0.4287 g, 0.00241 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (0.5443 g, 0.00200 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.0472 g, 0.0000408 mol) and 2.0 M aqueous sodium carbonate (2.4 mL, 0.0048 mol) in toluene (5 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with toluene then chloroform, 0.50 g. The material was dissolved in diethyl ether, washed with 0.10 M aqueous sodium hydroxide, water and brine. The organics were dried (K2CO3), and rotary evaporated to give 0.45 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 58-62° C.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:25][CH2:26][CH3:27])(C)(C)C.[OH-].[Na+]>C(O)C.C(Cl)Cl>[C:21]([O:20][C:18]([NH:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:9]([CH2:25][CH2:26][CH3:27])=[N:10][C:11]=2[CH:16]=1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCCc1nc2cc(NC(=O)OC(C)(C)C)ccc2n1CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCCc1nc2cc(NC(=O)OC(C)(C)C)ccc2n1CC(=O)O
Temperature: 70 °C

Procedure:
The product of step d.) was dissolved in 3 mL ethanol, treated with 1 M NaOH (500 μL), and heated to 70° C. for one hour. The reaction was diluted in DCM and extracted with water. The aqueous layer was acidified with 1 M HCl and extracted with DCM. The organic layer was washed with water, concentrated and purified by preparative LCMS to give the title compound. MS: ESI (positive): 334 (M+H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][O:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1
Reactant: OCc1cccs1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccs3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A toluene solution (1.74 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), 2-thiophenemethanol (0.237 ml), triphenyl phosphine (984 mg), and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred overnight at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-thienylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (620 mg, yield: 56%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-2.6-dimethoxypyridine gave 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.57 (d, 1H, J=8.7 Hz), 8.02 (d, 1H, J=2.7 Hz), 6.40 (d, 1H, J=8.1 Hz), 4.03 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3): −44640; LCMS: purity: 90%; MS (m/e): 285 (M+).