Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=4)(O)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:10](=[O:37])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2C3C(=CC=C(C(C4C=NC(Cl)=CC=4)(O)C4N(C)C=NC=4)C=3)[N:48](C)C(=O)C=2)C=CC=1>>[NH2:48][C:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:33][CH:34]1[CH2:36][CH2:35]1)[C:10](=[O:37])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1)c1ccc(Cl)cn1
Product: Cn1cncc1C(N)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1)c1ccc(Cl)cn1
Yield: 43 %

Procedure:
The same procedure was used as that in example 3, except that 4-(3-chloro-phenyl)-6-[(5-chloro-pyridin-2-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (258 mg, 0.486 mmol was used in the place of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one, to give the title compound as a white solid, 112 mg (0.21 mmol, 43% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH2:17]([O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=1[F:29])[CH3:18].C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]3([CH3:16])[CH3:15])=[CH:24][C:23]=1[F:29])[CH3:18]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-2,2,4,4-tetramethylchroman (0.204 g, 0.95 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.263 g, 0.86 mmol), triethyl amine, tetrahydrofuran, copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.21 g, 62%).
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][CH:14]1[CH2:19][C:18](=[O:20])[CH2:17][C:16](=O)[CH2:15]1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:16]1[CH2:15][CH:14]([CH3:13])[CH2:19][C:18](=[O:20])[CH:17]=1)([O:6][CH3:7])=[O:5]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: COC(=O)c1cccc(N)c1Br
Product: COC(=O)c1cccc(NC2=CC(=O)CC(C)C2)c1Br
Temperature: 125 °C
Yield: 66.6 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (10.2 g, 44.3 mM) and 5-methyl-1,3-cyclohexanedione (6.15 g, 48.7 mm) was heated at 125° C. under a stream of nitrogen for 1.5 hours. The resultant solid was triturated with ethyl acetate to afford 9.98 g (67%) of 3-(3-carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one. 1H NMR (CDCl3) δ 7.55 (m, 2H), 7.35 (dd, J=8 and 8 Hz, 1H), 6.4 (bs, 1H), 5.55 (s, 1H), 3.95 (s, 3H), 2.6-2.0 (m, 5H), 1.15 (d, J=7 Hz, 3H). MS (ES) m/e 338, 340.
Reaction SMILES: Br(F)(F)F.[Br:5]Br.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].S([O-])([O-])=O.[Na+].[Na+]>>[Br:5][C:12]1[CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc(Br)c1

Procedure:
A vigorously stirred mixture consisting of 0.1 moles (5 ml) bromine-trifluoride and 0.12 moles (6.5 ml) of bromine was added into a brine cooled three-necked flask equipped with a magnetic stirrer and a condenser containing ca. 0.6-0.7 moles of nitrobenzene. The addition was carried out dropwise with vigorous stirring while the temperature was kept between zero and ten degrees centigrate. After the addition was completed the crude reaction mixture was poured into a stirred icy 5% sodium sulfite solution. The organic layer was separated, and the aqueous solution was extracted twice with two portions of 100 ml dichloromethane. The combined organic layer was washed with 5% sodium bicarbonate solution and successively with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent evaporated. The crude reaction mixture was quantitatively analyzed by gas-chromatography internal standard program. The meta-bromonitrobenzene obtained was separated from the starting material by reduced pressure distillation. The yield of meta-bromonitrobenzene obtained, expressed in percentage of pure meta-bromonitrobenzene obtained based on reacted nitrobenzene, is 81%.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7][C:6]1=[NH:12])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C1COCC1>[CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7]/[C:6]/1=[N:12]\[C:30]([C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCCCN1CC(C)(C)SC1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN1CC(C)(C)S/C1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Yield: 9 %

Procedure:
To a solution of Example 2A (149 mg, 0.8 mmol) in THF (10 mL) was added triethylamine (0.4 mL) and adamantane-1-carbonyl chloride (0.2 g, 1 mmol). The mixture was heated to reflux overnight and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1 M NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate:hexanes) to provide 25 mg of the title compound. MS (ESI+) m/z 349 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3H), 1.19-1.36 (m, 2H), 1.39 (s, 6H), 1.51-1.61 (m, 2H), 1.61-1.73 (m, 6H), 1.74-1.81 (m, 6H), 1.89-2.02 (m, 3H), 3.40-3.44 (m, 2H), 3.55-3.64 (m, 2H); Anal. Calculated for C20H32N2OS: C, 68.92; H, 9.25; N, 8.04. Found: C, 68.94; H, 8.73; N, 8.02.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].OO.[Na+].[Cl-]>CCOCC.O.C1COCC1>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCC=CCCCCCCCC
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCC
Temperature: 25 °C
Yield: 94 %

Procedure:
8-tertial-buthytoxycarboniltetracyclo[4.4.0.12,5.17,10 ]-3-dodecene of 10 grams was mixed with dry THF of 25 milli-litter in a 200 milli-litter four-port flask, and the resultant material was cooled to 0 degree in centigrade. The ambience was replaced with argon, and THF solution of 1M boran-THF complex was dropped into the flask by 20 milli-litter. The solution was agitated at 0 degrees in centigrade for an hour and at room temperature for an hour. The resultant material was cooled to 0 degree in centigrade, and water was dropped by 3 milli-litter. Moreover, 3M water solution of NaOH and 30% solution of H2O2 were dropped by 6.6 milli-litter and 4.3 milli-litter, respectively at 20 degrees or less. The solution was agitated at room temperature for 1.5 hours, and water was saturated with NaCl. The resultant material was diluted with ether of 100 milli-litter. The ether layer was washed in saturated water solution of salt and water, and the resultant material was dried with MgSO4. The ether was distillated, and we obtained hydroxy-8-t-buthytoxycarboniltetracyclo[4.4.0.12,5.117,10 ]dodecane of 10 grams. The yield was 94 percent.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].[Li+].[OH-].O>C1COCC1>[OH:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cc[nH]c(=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc[nH]c(=O)c1O
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a heterogeneous solution of ethyl 3-hydroxy-2-oxo-1,2-dihydropyridine-4-carboxylate (200 mg, 1.09 mmol) (Intermediate 1B) in THF (3 mL) was added LiOH (26.1 mg, 1.09 mmol) and H2O (1 mL). The reaction mixture was stirred for 16 h. The reaction mixture was adjusted to pH 2 and filtered. The filter cake was evaporated to dryness to give Intermediate 17A (160 mg, 1.0 mmol, 94% yield). HPLC/MS (Method D) RT=0.45 min, [M+1]+ 155.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16](=[O:17])[C:10]3([CH2:14][CH2:13][O:12][C:11]3=[O:15])[S:9][C:8]=2[CH:18]=1)([O-])=[O:2]>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[OH:2][NH:1][C:4]1[CH:5]=[CH:6][C:7]2[C:16](=[O:17])[C:10]3([CH2:14][CH2:13][O:12][C:11]3=[O:15])[S:9][C:8]=2[CH:18]=1
Reactant: O=C1OCCC12Sc1cc([N+](=O)[O-])ccc1C2=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1OCCC12Sc1cc(NO)ccc1C2=O

Procedure:
In 35 ml of ethyl acetate and 3.5 ml of acetic acid was dissolved 356.3 mg of 6-nitro-4',5'-dihydrospiro[benzo[b]thiophen-2(3H),3'(2'H)-furan]-3,2'-dione as obtained in Reference Example 7, and was subjected to catalytic reduction under atmospheric pressure at room temperature in the presence of 113.3 mg of 5% palladium carbon. After absorption of hydrogen stopped, the catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure. Recrystallization of the residue from water-acetone (7:3) yielded yellow needles of 6-hydroxyamino-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione. Melting point: 184°-186° C.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:32]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:18]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([CH2:29][CH2:30][CH3:31])=[CH:27][CH:28]=5)[O:20][N:19]=4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH2:4][O:3]1.[Na+].[I-].CO>CC#N.[Si](Cl)(C)(C)C>[NH2:32][C:5]([CH2:8][N:9]1[C:17]2[C:12](=[C:13]([C:18]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][C:26]([CH2:29][CH2:30][CH3:31])=[CH:27][CH:28]=4)[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cn1
Yield: 48.8 %

Procedure:
To a solution of the product of Step E (0.018 g; 0.033 mmol), NaI (0.015 g; 0.0981 mmol) in anhydrous CH3CN (0.6 ml), Me3SiCl (0.08 ml) was added at room temperature with stirring under N2. After stirring for 30 min MeOH (0.5 ml) was added and solvents were removed under reduced pressure. The residue was purified by FCC (SiO2; NH4OH saturated CH2Cl2:MeOH 95:5) to give the title compound (0.0066 g; 49%) as colourless solid. 1H-NMR (CDCl3+CD3OD) 0.93 (tr, 3H, J=(Hz); 1.67-1.81 (m, 2H); 2.81 (tr, 2H, J=9 Hz); 2.99 (broad s, CD3OH); 3.07 (s, 2H); 3.26-3.65 (m, 8H); 6.74 (d, 1H, J=9 Hz); 7.15 (m, 1H); 7.31 (d, 1H, J=9 Hz); 7.42 (d, 1H, J=9 Hz); 8.32 (dd, 1H, J=3, 9 Hz); 9.33 (d, 1H, 3 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][P:9]([O:12][CH2:13][CH:14]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)([CH3:11])=[O:10]>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][P:9]([CH3:11])(=[O:10])[O:12][CH2:13][CH:14]1[CH2:17][NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(COP(C)(C)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CP(C)(=O)OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (120 mL) was added dropwise to the product of Step 1 (80 g) in dichloromethane (120 mL) at 0° C. over a period of 30 min. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction, reaction mixture was concentrated to remove excess trifluoroacetic acid under vacuum to afford azetidin-3-ylmethyl dimethylphosphinate TFA salt (90 g) as brown liquid. LC ESI: [M+H]+ m/z 164.2; HPLC purity; >97%. 1H NMR (400 MHz, CD3OD) S: 1.62 (s, 3H), 1.65 (s, 3H), 3.23-3.27 (m, 1H), 4.02 (dd, J=7.7, 11.1 Hz, 2H), 4.11-4.19 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:17]=[C:9]2[N:10]=[C:11](I)[N:12]=[C:13]([S:14][CH3:15])[N:8]2[N:7]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:17]=[C:9]2[N:10]=[C:11]([C:25]#[C:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=[C:13]([S:14][CH3:15])[N:8]2[N:7]=1
Reactant: CSc1nc(I)nc2nc(-c3ccco3)nn12
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(C#Cc2ccccc2)nc2nc(-c3ccco3)nn12
Reaction time: 3 h

Procedure:
To a solution of 2-(2-furyl)-5-iodo-7-methylthio-[1,2,4]triazolo[1,5-a][1,3,5]triazine (2.5 g) and phenyl acetylene (1.5 ml) in dimethylformamide (40 ml) was added triethylamine (1.1 ml), bis(triphenylphosphine)-palladium (II) chloride (0.2 g) and cuprous iodide (0.1 g) and the mixture stirred at room- temperature for 3 hours. The reaction mixture was diluted with water (350 ml) and extracted with ethyl acetate (3×50 ml). The organic extract was washed with water, dried magnesium sulphate and evaporated. The crude product was purified by chromatography on silica-gel (150 g), eluting with ethyl acetate dichloromethane (1% v/v). The residue from the fractions containing the product were triturated with ether and filtered to give 2-(2-furyl)-7-methylthio-5-phenylethynyl-[1,2,4]-triazolo[1,5-a][1,3,5]triazine (1.0 g). Crystallisation of an aliquot from isopropanol gave a yellow crystalline product m.p. 188°-190° C.; microanalysis, found: C, 60.8; H, 3.1; N, 20.9%, C17H11N5OS requires C, 61.2; H, 3.3; N,21.0%; NMR 2.8 (S, 3H, CH3S); 6.75 (d of d, 1H, furyl-4H); 7.35 (d, 1H, furyl-3H), 7.55 (complex, 3H, phenyl-3H, phenyl-4H and phenyl-5H), 7.74 (complex, 2H, phenyl-2H and phenyl-6H) and 8.0 (d, 1H, furyl-5H); m/e 353M+.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[O:12][C:11]([C:13](=[NH:16])OC)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:19](OC)[CH2:20][NH2:21]>C(#N)C>[ClH:1].[C:2]1([C:8]2[O:12][C:11]([C:13]3[NH:16][CH:19]=[CH:20][N:21]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=N)c1ccc(-c2ccccc2)o1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CC#N
Product: c1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1

Procedure:
A mixture of methyl 5-phenyl-2-furimidate hydrochloride (33 g, 0.14 mole), absolute alcohol (500 ml) and aminoacetaldehyde dimethyl acetal (15 g, 0.14 mole) was refluxed for 3 hr. The solvent was removed in a rotary evaporator and the residue was heated for 20 hr. at 63°-73° C with 3N HCl (400 ml). The solvent was decanted and the black viscous material was washed with water. It was purified by stirring with boiling acetonitrile and collected by filtration to give 4.1 g (9%). An analytical sample was prepared by recrystallization from acetonitrile m.p. >277° dec.
Reaction SMILES: [Na].Cl.[NH2:3][CH2:4][CH2:5][SH:6].NCCS.Cl.[CH3:12][N:13]([CH3:19])[CH2:14][C:15]#[C:16][CH2:17]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:12][N:13]([CH3:19])[CH2:14][C:15]#[C:16][CH2:17][S:6][CH2:5][CH2:4][NH2:3]
Reactant: NCCS
Reactant: CN(C)CC#CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CC#CCSCCN
Temperature: 0 °C
Yield: 43.7 %

Procedure:
Sodium (0.264 mol) was added in portions to ethanol (100 ml). When dissolution had occurred, the mixture was cooled to 0° C. and cysteamine hydrochloride (0.088 mol) was added with stirring. When all of the cysteamine had dissolved, 4-dimethylamino-1-chloro-2-butyne hydrochloride (0.088 mol) in ethanol (100 ml) was added dropwise with stirring whilst maintaining the temperature of the reaction mixture below 10° C. The reaction mixture was allowed to warm to room temperature overnight and evaporated under reduced pressure to afford an oil. This oil was taken up in aqueous solution (pH3), taken to pH8 with sodium bicarbonate and extracted with ethyl acetate. The aqueous layer was taken to pH12 and extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), filtered and evaporated to afford slightly impure 2-(4-dimethylamino-but-2-ynylthio)ethylamine as a reddish-brown oil (6.63 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC.[F-].[Cs+]>[Cu]I.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>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3ncccn3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (50 mg, 0.18 mmol), 2-(tributylstannyl)pyrimidine (65 mg, 0.18 mmol), CuI (8 mg, 0.04 mmol), CsF (81 mg, 0.53 mmol), and Pd(PPh3)4 (10 mg, 8.9 μmol). The vial was capped with a septum screw-cap and then placed under N2 atmosphere. To the vial was added degassed DMF (1 mL). The vial was placed in a 80° C. heating block with stirring for 1 hour. The mixture was allowed to cool to room temperature, and the reaction mixture was then directly subjected to C18 chromatography (water:MeOH w/0.1% TFA) to afford 2-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)pyrimidine as an amber solid. This material was carried forward into step 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12.CC(C)([O-])C.[Na+].[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C1COCC1.CN(C=O)C>[Br:23][C:19]1[CH:18]=[C:17]([C:16]2[C:3]3[C:4](=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]=3[NH:1][S:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)(=[O:39])=[O:38])[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(Br)c3)c2c1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2scc(-c3cccc(Br)c3)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a stirred solution of ethyl 4-amino-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 46) (2.87 g, 7.33 mmol) in THF (30 mL) and DMF (15 mL) was added sodium tert-butoxide (1.762 g, 18.34 mmol) and 3-chlorobenzenesulfonyl chloride (2.066 mL, 14.67 mmol). The reaction mixture was then stirred at RT under nitrogen for ca. 30 min and then quenched with saturated ammonium chloride solution (ca. 60 mL). The mixture was extracted with DCM (ca. 30 mL×5) and the combined organics dried and concentrated in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in DCM afforded the title compound (1.48 g). LCMS (A) m/z: 566/568 [M+1]+, Rt 1.47 min (acidic).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[N:30]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]([NH:20][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=5)=[O:9])[CH:42]=[CH:41][CH:40]=4)=[N:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 77.5 %

Procedure:
Using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (100 mg, 0.515 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (60 μL, 0.7 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (122.5 mg, 0.396 mmol), triethylamine (120 mg, 1.19 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (149 mg, 78%) was obtained as a white powder.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].N1C=CN=C1.Cl[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A solution of 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see intermediate 47) (659 mg, 1.586 mmol) and imidazole (216 mg, 3.17 mmol) in N,N-dimethylformamide (DMF) (20.0 mL) was treated with chloro(1,1-dimethylethyl)dimethylsilane (0.330 mL, 1.903 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. Another equivalent of imidazole (216 mg, 3.17 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (0.330 mL, 1.903 mmol) were then added to the reaction which was stirred at room temperature for 1 h then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed twice with brine, dried over MgSO4, and concentrated in vacuovacuo. Purification of the residue on SP4 using a 50 G silica cartridge (gradient:10 to 50% AcOEt in Hexanes) gave 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (599 mg, 1.085 mmol, 68.4% yield).
Reaction SMILES: CO.[ClH:3].[CH2:4]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[F:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC>[ClH:3].[CH2:4]([NH:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[F:25])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: F[C@@H]1CNCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
MeOH (25 mL) and HCl (4 N in dioxane) (16 ml, 64.00 mmol) were added to a flask charged with (3R,4S)-tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate (4 g, 12.97 mmol, prepared according to WO2007/071965 and references described therein) and the suspension was stirred at RT for 5 h. The solution was concentrated under reduced pressure and the white solid obtained was suspended in ether (50 ml) and filtered, dried under high vacuum to give the title product (2.90 g, 91%) (white solid).