Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].N1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1>O1CCOCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=2)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Reactant: CSc1cccc(N)c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSc1cccc(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
A solution of 3-(methylsulfanyl)aniline (658 mg, 4.73 mmol) and pyridine (995 uL, 18.9 mmol) was cooled to 0° C. under N2 before the dropwise addition of bis(trimethylsilyl)trifluorocetamide (1.76 mL, 9.45 mmol) over 5 min. After stirring for 5 min at 0° C., a solution of 4-fluoro-2-nitrobenzenesulfonyl chloride (1.19 g, 4.97 mmol) in 1,4-dioxane (7 mL) was added dropwise over 15 min. The mixture was stirred at rt for 1 h, then at 100° C. for 30 min. After cooling to rt, the mixture was concentrated in vacuo and partitioned between DCM and 1M aqueous HCl (25 mL each). The phases were separated and the aqueous layer extracted with DCM (2×25 mL). The combined organic layers were concentrated in vacuo and purified by gradient flash chromatography, eluting with 5-50% EtOAc in heptane to yield the title compound (865 mg, 2.53 mmol).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18]Br>CS(C)=O.O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:18][CH2:17]1)#[N:2]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol) in dimethyl sulfoxide (30 mL) was added sodium hydride (60% in oil, 1.0 g, 26 mmol) while cooling to not more than 25° C. without causing solidification. The reaction mixture was stirred at room temperature for 30 min, 1,2-dibromoethane (2.4 g, 12.8 mmol) was added, and the mixture was further stirred at room temperature for 10 hr. The reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (1.3 g, 76%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>O.C(O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:30])=[O:4])[CH2:16][CH2:17]2)=[CH:22]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 60 °C

Procedure:
A solution of 1.33 g (33 mmol) of sodium hydroxide in 120 mL of water was added to a suspension of 6.31 g (16.6 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared in Example 1, part D) in 120 mL of ethanol. This mixture was heated at 60° C. for 3 hours and the solvent was removed under reduced pressure. After addition of 50 mL of water, the crude mixture was neutralised with HCl 2N and the solid formed was isolated. After recrystallisation from acetonitrile, 2.6 g (43% of yield) of a white solid corresponding to the desired product were obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH3:10]>>[CH2:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH3:10]
Reactant: O=Cc1ccc(Br)s1
Reactant: CCB(O)O
Product: CCc1ccc(C=O)s1
Yield: 50.6 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and ethylboronic acid (160 mg, 2.16 mmol) in place of hexylboronic acid to give 5-ethylthiophene-2-carbaldehyde (93 mg, 51%). Used without further characterization.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[O:26][CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Reactant: BrCC1CC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CC3)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 2-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-5-chloro-phenol (Example 48, intermediate a) and bromomethyl-cyclopropane (CAS Reg. No. 7051-34-5). Colorless powder (70%). MS (Turbo Spray): m/z=425.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:21])([F:20])[CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([O:5][C:6]([CH2:8][C:9]([CH2:18][CH2:17][CH2:16][C:15]([F:21])([F:20])[F:14])([C:12]#[N:13])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(C#N)C#N
Reactant: FC(F)(F)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(C#N)(C#N)CCCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
0.48 g of 2-(tert-butoxycarbonylmethyl)malononitrile and 0.32 g of 1,1,1-trifluoro-4-bromobutane were dissolved in 2 ml of N,N-dimethylformamide, and to the solution was added 0.40 g of potassium carbonate followed by stirring for 5 hours at room temperature. Then, to the reaction mixture was added dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 0.33 g of 2-(tert-butoxycarbonylmethyl)-2-(4,4,4-trifluorobutyl)malononitrile (hereinafter referred to as the present invention compound (51)).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:5]([O:20]C)[CH:4]=1)#[N:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:5]([OH:20])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1NS(=O)(=O)Nc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(NS(=O)(=O)Nc2ccccc2)c(O)c1
Temperature: 25 °C

Procedure:
To a solution of N-(4-cyano-2-methoxyphenyl)amino sulfonyl aniline (1 mmol) in methylene chloride (1 mL) at −78° C. is added boron tribromide (3 mmol) and the reaction is warmed to rt. Upon completion of the reaction, the reaction is quenched with water (1 mL) and concentrated. The crude material is purified by either recrystalization or chromatography to give N-(4-cyano-2-hydroxyphenyl)amino sulfonyl aniline.
Reaction SMILES: Cl([O-])=O.[Na+].CC(=CC)C.P([O-])(O)(O)=[O:11].[Na+].[F:16][C:17]([F:46])([F:45])[C:18]1[CH:44]=[CH:43][CH:42]=[CH:41][C:19]=1[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH2:38][CH:39]=[O:40])[N:35]=[N:34]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1>O.CC(C)=O>[F:46][C:17]([F:45])([F:16])[C:18]1[CH:44]=[CH:43][CH:42]=[CH:41][C:19]=1[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH2:38][C:39]([OH:11])=[O:40])[N:35]=[N:34]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1
Reactant: O=CCc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)Cc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 10-mL round-bottom flask equipped with a magnetic stirbar was added sodium chlorite (28 mg, 0.31 mmol), 2-methyl-2-butene (32 μL, 0.31 mmol) and sodium dihydrogen phosphate (37 mg, 0.31 mmol) in water (1.0 mL). To this solution was added [1-(2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl]acetaldehyde (22 mg, 0.05 mmol) dissolved in acetone (1.0 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated, poured into a 50-mL separatory funnel containing saturated aqueous KH2PO4 solution (30 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give the desired product.
Reaction SMILES: [CH2:1]([O:5][P:6](Cl)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4].[O-:14][C:15]#[N:16].[Na+]>C(#N)C>[CH2:1]([O:5][P:6]([N:16]=[C:15]=[O:14])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOP(=O)(Cl)OCCCC
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCOP(=O)(N=C=O)OCCCC

Procedure:
Analogously to Example 1, 200 g of dibutoxyphosphinic acid chloride were reacted with 58 g of sodium cyanate in 350 ml of absolute acetonitrile. 142 g of a faintly yellowish liquid (69% of theory) having a boiling point of 80°-83° C./0.67 Pa were isolated.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: CNCCO
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2) and 2-methylamino-ethanol to afford as a white crystalline solid. HPLC (Condition 4) tR=5.72 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=452.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH2:16][CH2:15][CH2:14][CH:13]=1)=[O:11].[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:8][O:9][C:10]([C@:12]12[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:30][N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:25]2)=[O:11]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)C1=CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]12CCC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 82.5 %

Procedure:
A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclopentene-1-carboxylic acid methyl ester (2.52 g, 20.0 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (5.00 g, 21.1 mmol) in dichloromethane (40 mL) at room temperature, and the mixture was heated with stirring at room temperature for 15.5 hours. The reaction solution was diluted with dichloromethane (100 mL) and washed with a saturated sodium bicarbonate solution (80 mL). The washed aqueous layer was further extracted with dichloromethane (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→90:10→80:20) to give 4.28 g (83%) of the title compound as a colorless transparent oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[C:6]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[N:5]=[C:4]([NH:29][C:30]2[CH:35]=[C:34]([CH3:36])[C:33]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][O:45][CH3:46])[CH2:39][CH2:38]3)=[CH:32][C:31]=2[O:47][CH:48]([CH3:50])[CH3:49])[N:3]=1.[NH2:51][NH2:52]>C1COCC1>[CH:48]([O:47][C:31]1[CH:32]=[C:33]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][O:45][CH3:46])[CH2:39][CH2:38]2)[C:34]([CH3:36])=[CH:35][C:30]=1[NH:29][C:4]1[N:3]=[C:2]2[NH:51][N:52]=[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[C:6]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[N:5]=1)([CH3:50])[CH3:49]
Reactant: COCCN1CCC(c2cc(OC(C)C)c(Nc3nc(Cl)c(C(=O)c4ccccc4)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc2C)CC1
Reactant: NN
Solvent: C1CCOC1
Product: COCCN1CCC(c2cc(OC(C)C)c(Nc3nc(Nc4ccccc4S(=O)(=O)C(C)C)c4c(-c5ccccc5)n[nH]c4n3)cc2C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL microwave reaction tube was added (4-chloro-2-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenylamino)-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone (0.0548 mmol), THF (4 mL) and H2NNH2 (0.4 mL). The resulting mixture was stirred at 120° C. for 30 minutes by using a microwave machine. The reaction solution was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford N6-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine as a slightly yellow solid. MS (ES+): 698.30 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:16][C:11]1[C:10]([CH3:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
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+]
Product: Cc1c(Oc2ccnc(-c3cnn(C)c3)c2)ccc(N)c1F
Yield: 75.2 %

Procedure:
Using a procedure analogous to Example A1, 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (1.0 g, 3.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.8 mmol), Na2CO3 (0.84 g, 6.6 mmol) and Pd(PPh3)4 (0.25 g, 0.2 mmol) were combined to give 2-fluoro-3-methyl-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (0.74 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=6.4 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.68-6.61 (m, 2H), 6.45 (dd, J=5.6, 2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 299.2 [M+H]+.
Reaction SMILES: O[C:2]1[S:3][C:4](I)=[CH:5][C:6]=1C.CN(C)[CH:11]=[O:12]>>[OH:12][CH2:11][C:2]1[S:3][C:4]([C:4]2[S:3][C:2]([CH2:11][OH:12])=[CH:6][CH:5]=2)=[CH:5][CH:6]=1
Reactant: Cc1cc(I)sc1O
Reactant: CN(C)C=O
Product: OCc1ccc(-c2ccc(CO)s2)s1

Procedure:
5,5'-Dihydroxymethyl-2,2'-bithiophene was also obtained by refluxing 2-hydroxy-methyl-5-iodo-thiophene with Cu powder in dimethyl formamide. The Ullmann condensation yielded a very poor amount of 5,5'-dihydroxymethyl-2,2'-bithiophene.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[C:14]([O:18][CH2:19][C@H:20]([CH3:47])[O:21][C:22]1[CH:23]=[C:24]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH:35]=1)[C:25]([O:27][NH2+]C(C)(C)C)=[O:26])([CH3:17])([CH3:16])[CH3:15].CC(OC)(C)C>O>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[C:14]([O:18][CH2:19][C@H:20]([CH3:47])[O:21][C:22]1[CH:23]=[C:24]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH:35]=1)[C:25]([OH:27])=[O:26])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O[NH2+]C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: COC(C)(C)C
Solvent: O
Product: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aqueous citric acid was prepared by dissolving citric acid (7.35 g, 38.25 mmol) in water (100 mL). The aqueous citric acid solution was added to a reaction vessel containing ({3[(1S)-2-tert-butoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzoyl}oxy)(tert-butyl)ammonium (10 g at 94.6% w/w, 19.13 mmol) and MTBE (80 mL). The two-phase mixture was stirred for 30 minutes at ambient temperature. The two phases were separated, and the aqueous phase was extracted with MTBE (80 mL). The two organic phases were combined and washed three times with brine (3×80 mL), followed by water (2×80 mL). The combined MTBE extract was distilled down to low volume, fresh MTBE (80 mL) was added and the mixture was distilled down to low volume. Acetonitrile (120 mL) was added and the mixture was distilled down to low volume at 50° C., 209 mbar. This azeodrying was repeated once more to provide a dry acetonitrile solution of the title compound, which was used directly in the next stage.
Reaction SMILES: [Cl-].[OH:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30]([C:32]1[N:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)=O.O1CCCC1.CC(C)([O-])C.[K+]>O>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:30][C:32]2[N:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:28][CH:29]=1
Reactant: OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3ccc(CO)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a mixture of [4-(hydroxymethyl)benzyl](triphenyl)phosphonium chloride (1.283 g, 3.064 mmol), tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (876.3 mg, 3.008 mmol) and anhydrous tetrahydrofuran (10 ml) was added potassium tert-butoxide (383.9 mg, 3.421 mmol), and the mixture was stirred at room temperature for 1 hr. Water (20 ml) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1). The fraction containing the target product was concentrated and the obtained solid was dissolved in ethyl acetate, and extracted twice with 0.2M hydrochloric acid. The aqueous layer was saturated with sodium carbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 4-(6-{2-[4-(hydroxymethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (850.2 mg, yield 71.5%, E/Z mixture) as a pale-yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)O1.[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.O.C([O-])([O-])=O.[K+].[K+]>COCCOC.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:19][C:20]1[N:24]=[C:23]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[S:22][N:21]=1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1nsc(Cl)n1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Clc1nsc(-c2ccc3[nH]ccc3c2)n1
Temperature: 85 °C
Yield: 35.1 %

Procedure:
To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (2 g, 8.23 mmol, Aldrich) and 3,5-dichloro-1,2,4-thiadiazole (1.27 g, 8.23 mmol, Aldrich) in 1,2-dimethoxy ethane (30 mL)/H2O (10 mL) was added K2CO3 (2.27 g, 16.46 mmol) and Pd(PPh3)4 (0.95 g, 0.82 mmol). N2 gas was purged for 15 min through the mixture. The reaction was heated at reflux at 85° C. for 6 h. The mixture was cooled to RT and quenched with H2O (100 mL) and was extracted with EtOAc (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica-gel column chromatography (eluent: 5% EtOAc in petroleum ether) to give 3-chloro-5-(1H-indol-5-yl)-1,2,4-thiadiazole (680 mg, 35.5%) as an off white solid. MS (ESI, pos. ion) m/z: 236 (M+1); 1H-NMR (300 MHz, CDCl3): δ 8.5 (brs, 1H), 8.29 (d, J=0.8 Hz, 1H), 7.78 (dd, J=8.4, 1.8 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.32-7.31 (m, 1H), 6.67 (t, J=2.1 Hz, 1H).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9]>CN(C)C=O>[CH:8]([C:7]1[CH:6]=[CH:5][C:12]([O:13][CH3:14])=[C:11]([CH:10]=1)[C:2]#[N:3])=[O:9]
Reactant: N#C[Cu]
Reactant: COc1ccc(C=O)cc1Br
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1C#N
Temperature: 120 °C
Yield: 66.7 %

Procedure:
Add copper (I) cyanide (4.58 g, 51.2 mmol) to a solution of 3-bromo-4-methoxy-benzaldehyde (10.0 g, 46.5 mmol) in N,N-dimethylformamide (0.2 M). Heat the solution to 120° C. and stir the solution for 1d. Quench with potassium carbonate (sat) and extract with diethyl ether (5×). Wash organic layers with water, dry with sodium sulfate, and concentrate to afford the title compound (5.00 g, 31.0 mmol, 67%): 1H NMR (400 MHz, DMSO-d6) δ 4.04 (s, 3H), 7.47 (d, J=8.6 Hz, 1H), 8.20 (m, 1H), 8.33 (m, 1H), 9.91 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2F)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2F)n(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.30 g (6.67 mmol) of the compound of Example 36A are provided in 32 ml of a 2:1 mixture of 1,4-dioxane and water, 17 ml (33.4 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 50° C. for 2 h. The mixture is concentrated, a 2N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with ethyl acetate, and the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is stirred in a little of a mixture of petroleum ether and diethyl ether, collected by filtration and dried under high vacuum. 1.58 g (75% of theory) of the title compound are obtained.