Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19](Br)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:32]([SiH:36]([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>CN1CCCC1=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([Si:36]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37])=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[SiH](C)C(C)(C)C
Reactant: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)c1ccc2c(c1)cc(C(=O)Nc1ccc(N3CCC3)nc1)n2Cc1cccc(F)c1
Yield: 17.5 %

Procedure:
Compound No. 18 was prepared according to a process similar to that described in stage 8.4, by reacting 0.15 g (0.31 mmol) of N-[6-(azetidin-1-yl)pyridin-3-yl]-5-bromo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in stage 17.3, with 108 mg (0.93 mmol) of tert-butyldimethylsilane in the presence of 0.2 g (0.94 mmol) of potassium triphosphate and of 16 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium in 2 ml of dry 1-methyl-2-pyrrolidinone (NMP). 28 mg of the expected product are obtained.
Reaction SMILES: Cl.N[C@H](C)CSC1SC2C=CC=CC=2N=1.SC1SC2C=CC=CC=2N=1.C(O[C@@H]1[C@H](OC(=O)C2C=CC=CC=2)[C@@H](COC(=O)C2C=CC=CC=2)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C1C=CC=CC=1.C([O:78][C@@H:79]1[C@H:83]([O:84]C(=O)C2C=CC=CC=2)[C@@H:82]([CH2:93][O:94]C(=O)C2C=CC=CC=2)[O:81][C@H:80]1[N:103]1[C:125]2[N:124]=[C:123]([Cl:126])[N:122]=[C:107]([NH:108][C@H:109]([CH3:121])[CH2:110][S:111][C:112]3[S:113][C:114]4[CH:120]=[CH:119][CH:118]=[CH:117][C:115]=4[N:116]=3)[C:106]=2[N:105]=[CH:104]1)(=O)C1C=CC=CC=1>N>[Cl:126][C:123]1[N:122]=[C:107]([NH:108][C@H:109]([CH3:121])[CH2:110][S:111][C:112]2[S:113][C:114]3[CH:120]=[CH:119][CH:118]=[CH:117][C:115]=3[N:116]=2)[C:106]2[N:105]=[CH:104][N:103]([C:125]=2[N:124]=1)[C@@H:80]1[O:81][C@H:82]([CH2:93][OH:94])[C@@H:83]([OH:84])[C@H:79]1[OH:78]
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[C@@H](N)CSc1nc2ccccc2s1
Agent: Cl
Agent: N
Product: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 24 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (2.5 g, 14 mmol) and 2-mercaptobenzothiazole (2.3 g, 14 mmol) followed by acidic hydrolysis] (1.7 g, 5.7 mmol) with 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.8 g, 4.5 mmol), followed by debenzoylation of the purified 2',3',5'-tri-O-benzoyl-2-chloro-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosine in methanolic ammonia (200 ml) (previously saturated at -10° C.) to provide the title 2-chloro-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosine (1.05 g, 24%) (following column chromatography), 1H NMR (DMSO-d6) δ 1.38 (3H, d, --CHCH3), 3.50-3.68 (4H, m, H-5'a and H-5'b and --CH2 --), 3.95 (1H, d, H-4'), 4.12 (1H, d, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.34, 7.45 (2H, 2t, Ar-H), 7.85, 7.98 (2H, 2d, Ar-H), 8.40 (1H, s, H-8), 8.53 (1H, d, N--H). HPLC retention time 16.6 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [Br:1]Br.[Br:3][CH:4]([CH3:12])[CH2:5][C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH3:8]>C(Cl)(Cl)Cl>[Br:1][CH2:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[CH2:5][CH:4]([Br:3])[CH3:12]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CC(C)Br
Solvent: ClC(Cl)Cl
Product: CC(Br)CC(C)(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
20.9 g (0.13 mole) of bromine are added dropwise to 27 g (0.13 mole) of 5-bromo-3,3-dimethyl-2-hexanone in 50 ml of chloroform at room temperature. The mixture is subsequently stirred at room temperature for 30 minutes, washed with water, dried over sodium sulphate and concentrated in vacuo. 36.9 g (99% of theory) of 1,5-dibromo-3,3-dimethyl-2-hexanone of refractive index nD20 =1.5015 are obtained.
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>C1COCC1>[CH:17]1([C:16]2[CH:15]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:23][CH2:24][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Solvent: O
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2CCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 67.8 mmol of fluorenyllithium in 50 cm3 of THF was added at room temperature to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of THF. After stirring at room temperature for 2 hours, 60 cm3 of water were added. The resulting precipitated substance was filtered off with suction, washed with diethyl ether and dried at an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)ethylbenzene (correct elemental analyses; 1H-NMR spectrum) were obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[N:13][N:12]([CH3:15])[C:11]=2[CH2:16][OH:17])=[CH:6][CH:5]=1.Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1>C1COCC1>[CH3:28][O:27][C:25]([C:22]1[CH:21]=[N:20][C:19]([O:17][CH2:16][C:11]2[N:12]([CH3:15])[N:13]=[N:14][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)=[CH:24][N:23]=1)=[O:26]
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2c(-c3ccc(F)cc3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a suspension of NaH (55% in oil, 131 mg, 3.0 mmol) in THF (3.9 mL) was added a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (622 mg, 3.0 mmol) in THF (7.9 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 30 min. Then a solution of methyl 5-chloropyrazine-2-carboxylate (569 mg, 3.3 mmol) in THF (7.9 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane, then 0 to 5% methanol in dichloromethane) afforded the title compound (474 mg, 46%) as an off white gum. MS: m/e=344.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[CH2:13][C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[N:22]=2)[CH:17]=[N:16][CH:15]=1)=[O:5].O.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[CH2:13][C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[CH:24][NH:23][N:22]=2)[CH:17]=[N:16][CH:15]=1)=[O:5]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CN3C[C@@H]4C[C@H]3CN4C(=O)c3cccc(Cl)c3Cl)n2)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(Cl)c1Cl)N1C[C@@H]2C[C@H]1CN2Cc1cncc(Nc2cc[nH]n2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
19 mg of 6-(((1S,4S)-5-(2,3-dichlorobenzoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazine-2-amine was dissolved in 1 ml of trifluoroacetic acid and 0.1 ml of water followed by stirring at room temperature for 15 hours. The reaction solution was concentrated in vacuo, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate, water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=5/1) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)=[CH:4][C:3]=1[CH3:18].[NH2:19][C:20]([NH2:22])=[O:21]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:15]=[C:14]([CH3:16])[O:13][N:12]=3)[NH:22][C:20](=[O:21])[N:19]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(/C=C/C(=O)c2ccc(O)c(C)c2)no1
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3ccc(O)c(C)c3)nc(=O)[nH]2)no1
Temperature: 120 °C
Yield: 4 %

Procedure:
A mixture of (E)-1-(4-hydroxy-3-methylphenyl)-3-(5-methylisoxazol-3-yl)prop-2-en-1-one (200 mg, 0.8 mmol) and urea (56 mg, 4.0 mmol) in 4M HCl/dioxane (5 mL) was heated to 120° C. in a sealed vessel overnight. After cooling, the crude reaction mixture was purified by reverse-phase HPLC to give 9 mg of product.
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:26][CH2:27][N:28]([C:2]2[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]3[O:9][CH:8]([CH3:10])[CH2:7][C:6]=3[C:11]=2[CH3:12])[CH2:29][CH2:30]1
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)O2
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)c(OC)c1
Yield: 53.7 %

Procedure:
By using 5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (480 mg, 1.88 mmol) synthesized in Reference example 53 and 1-(2,4-dimethoxyphenyl)piperazine (627 mg, 2.82 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 400 mg (yield 54%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:18]=2[N:19]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: NCCc1ccc2c(c1)OCO2
Product: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH:13]([CH3:15])[CH3:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Li+]>COCCOC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:3][OH:2])[CH:13]([CH3:14])[CH3:15])=[O:7])([CH3:11])([CH3:12])[CH3:10]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
This compound was prepared in 81% yield from the ester 4b (9.28 g, 40 mmol) by reduction with lithium borohydride in dry DME following the procedure that has been described earlier1,2. TLC Rf 0.47 (eluent MeOH/CHCl3,7/93). 1H NMR (CDCl3) δ 0.91 and 0.98 (dd, J=2 Hz, 6H, CH3CHCH3), 1.44 (s, 9H, t-Bu), 1.45-1.97 (m, 1H, CH3CHCH3), 2.15 (s, 1H, OH), 3.24-3.49 (m, 1H, CHCH2), 3.53-3.72 (m, 2H, CH2OH), 4.36-4.77 (m, 1H, NH). CI MS, m/e 204 (M+ +1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]=[C:28]=[O:29].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:26][NH:27][C:28](=[O:29])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCCC1c1cccc(O)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a solution of 2-{2-[2-(3-hydroxyphenyl)-1-pyrrolidinyl]ethyl}-1H-isoindole- 1,3(2H)dione (0.71 g) in dry tetrahydrofuran (35 ml) was added methyl isocyanate (0.13 ml) followed by milled potassium carbonate (0.38 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 45 mins, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated, and the residue was triturated with petroleum ether. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/heptane). The appropriate fractions were collected and concentrated to afford 0.78 g (94%) of product. Recrystallization from dichloromethane/petroleum ether gave the analytical sample, mp 96°-98° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH:13]=O>[Pd].CO.O>[CH2:13]([N:1]([CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: CC(C)(C)CC=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(C)CCN(CCC(C)(C)C)[C@@H](CC(=O)O)C(=O)O

Procedure:
To a slurry of L-aspartic acid (4 g, 0.03 mol) in 1:1 methanol/water (80 mL) was added neat 3,3-dimethylbutyraldehyde (3 g, 0.03 mol), followed by Pd/C (4%, 50% wet, 0.5 g). The mixture was hydrogenated using H2 (50 psi) at room temperature for 2 days. The resulting reaction mixture was filtered through a Celite® bed, and the bed washed with methanol (50 mL) The filtrate and washings were combined and the methanol removed using a rotary evaporator under reduced pressure at 40-50° C. to provide the N,N-di-neohexyl L-aspartic acid as a solid precipitate in water. The solid was filtered, washed with water (2 mL) and dried in a vacuum oven at 50° C. for 4 hrs to provide 3.2 g of N,N-di-neohexyl L-aspartic acid (36%), M.P. 197-198° C., [α]D -3 (c=1, methanol). Anal. Calc'd. for C16H31NO4 ; C, 63.78; H, 10.29; N, 4.65. Found: C, 63.43; H, 10.29; N, 4.70
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([SH:9])[N:4]=1.[OH-].[Na+].CI.[CH2:16](Cl)Cl>C1COCC1>[CH3:16][S:9][C:5]1[N:4]=[C:3]([C:2]([F:10])([F:1])[F:11])[CH:8]=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccnc(S)n1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(trifluoromethyl)pyrimidine-2-thiol (1.08 g, 6.0 mmol) in THF (40 mL) was added 1N NaOH (10 mL), followed by the addition of MeI (0.8 mL). The reaction mixture was stirred at room temperature overnight, followed by addition of CH2Cl2. The organic layer was washed with saturated NaHCO3, H2O, and saturated NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes: EtOAc=1:10) to give 2-(methylthio)-4-(trifluoromethyl)pyrimidine as colorless oil (0.6 g). This colorless oil was dissolved in CH2Cl2, and to the solution mCPBA (1.8 g) was added. The resulting mixture was stirred at room temperature for 3 h. To the reaction mixture saturated Na2SO4 (10 mL) was added, followed by the addition of saturated Na2CO3. The aqueous portion was extracted with CH2Cl2 twice and the organic portions were dried over Na2SO4, filtered, and concentrated to give 2-(methylsulfonyl)-4-(trifluoromethyl)pyrimidine as white solids (0.64 g, 46% yield for two steps,). LC-MS RT=1.19 min, [M+Na] 249.06 (LCMS Method 1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)O1.[NH2:16][C:17]1[CH:22]=[N:21][C:20](Br)=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[NH2:16][C:17]1[N:18]=[CH:19][C:20]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)=[N:21][CH:22]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC1(C)OB(C2=CC(=O)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: Nc1cnc(C2=CC(=O)CC2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone (2.99 g, 14.37 mmol) (the filtrate from last step) was added 2-amino-5 bromopyrazine (2.5 g, 14.37 mmol), PdCl2(dppf)-CH2Cl2 (1.173 g, 1.437 mmol), Na2CO3 (7.61 g, 71.8 mmol) and water (17.96 mL) the reaction mixture was stirred at 100° C. oil bath for overnight, filtered through Celite. The reaction mixture was then extracted by EtOAc. The organic was then used 3N HCl (20 mL) washed 2 times, and water 50 mL once, the AQ was then neutralized by NaOH to pH=8, the reaction mixture was then extracted by CHCl3/IPA (7:3) 3 times, the organic was dried and concentrated and used as it. LCMS (m/z): 176.1 (MH+), 0.32 min.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:30]([C:31]#[N:32])=[CH:29][C:10]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][C@H:15]2[O:27][CH3:28])=[O:12])=[C:9]([O:33][CH3:34])[CH:8]=1.[OH-:35].[NH4+]>>[NH2:6][C:7]1[CH:8]=[C:9]([O:33][CH3:34])[C:10]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][C@H:15]2[O:27][CH3:28])=[O:12])=[CH:29][C:30]=1[C:31]([NH2:32])=[O:35]
Reactant: COc1cc(N)c(C#N)cc1C(=O)N[C@H]1CCN(Cc2ccccc2)C[C@H]1OC
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: COc1cc(N)c(C(N)=O)cc1C(=O)N[C@H]1CCN(Cc2ccccc2)C[C@H]1OC
Reaction time: 8 h

Procedure:
285 Parts of sulfuric acid were cooled in an ice-bath and 15.5 parts of cis-4-amino-5-cyano-2-methoxy-N-[3-methoxy-1-(phenylmethyl)-4-piperidinyl]benzamide were added portionwise while cooling. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto ice-water and the whole was alkalized with ammonium hydroxide. The product was filtered off and stirred in a mixture of trichloromethane and water. The product was filtered off again and dried, yielding 15.0 parts of cis-4-amino-6-methoxy-N1 -[3-methoxy-1-(phenylmethyl)-4-piperidinyl]-1,3-benzenedicarboxamide (compound 236).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.Cl>O1CCCC1.C(OCC)(=O)C>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[P:2]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccccc1-c1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
12.3 g (52.4 mmol) of 6-chloro-6H-dibenz[c,e][1,2]oxa-phosphorine in 80 ml of anhydrous tetrahydrofuran are introduced, in an argon atmosphere with stirring, and 66 ml of a 2M solution of phenylmagnesium bromide in tetrahydrofuran are added dropwise. The temperature increases in the course of this from 25° to 40° C. The mixture is then stirred for 4 hours at 65° C., cooled to room temperature and 100 ml of water and 100 ml of ethyl acetate are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 19.0 g of colorless oil are obtained. By crystallization with methanol/water, 10:1, 18.1 g (98%) of colorless crystals having melting point 123° to 124° C. are obtained.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].Cl.[NH:6]1[CH2:9][CH:8]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:13])=[O:12])[CH2:7]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[CH:2]([N:6]1[CH2:9][CH:8]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:12])=[O:13])[CH2:7]1)([CH3:4])[CH3:3]
Reactant: O=C(NCCS(=O)(=O)NC1CNC1)c1ccc(Cl)s1
Reactant: CC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
85.3 mg (5 equiv.) 2-Bromo-propane were added to a mixture of 50 mg (0.14 mmol) 5-chloro-thiophene-2-carboxylic acid[2-(azetidin-3-ylsulfamoyl)-ethyl]-amide hydrochloride and 38 mg (2 equiv.) K2CO3 in 5 ml DMF. The resulting mixture was stirred for 2 h at 70° C., then diluted with 15 ml dichloromethane and washed with 3 ml of a saturated NaHCO3-solution. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-azetidin-3-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15].[CH3:20][CH:21]([CH2:39][CH3:40])[CH2:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34].C([O-])([O-])=O.[K+].[K+].N#N.[C-]#N.[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.O>[CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])=[C:24]([O:23][CH2:22][CH:21]([CH3:20])[CH2:39][CH3:40])[CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15]
Reactant: CCC(C)COc1ccc(Br)cc1OCC(C)CC
Reactant: CCC(C)COc1ccc(B(O)O)cc1OCC(C)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)COc1ccc(-c2ccc(OCC(C)CC)c(OCC(C)CC)c2)cc1OCC(C)CC

Procedure:
229.405 g (696.6 mmol) of 3,4-bis(2-methylbutyloxy)-1-bromobenzene, 215 g (731 mmol) of 3,4-bis(2-methylbutyloxy)benzeneboronic acid and 202.1 g (1.462 mol) of K2CO3 were suspended in 800 ml of toluene and 800 ml of water and the mixture was saturated with N2 for 1 hour. 1.74 g (1.505 mmol) of Pd(PPh3)4 was subsequently added under protective gas. The turbid, slightly yellowish mixture was stirred vigorously under reflux for about 7 hours under nitrogen. After cooling, the organic phase was stirred with 500 ml of 1% strength NaCN solution. The phases were separated and the organic phase was washed with water, dried over Na2SO4 and evaporated on a rotary evaporator. This gave 339 g (679.7 mmol, 98%) of a light-brown oil which, according to 1H NMR, had a purity of 97% and was used directly in the subsequent reaction.