Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:47]([C:49]([CH3:51])=[O:50])=[CH2:48].CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:48]=[CH:47]/[C:49](=[O:50])[CH3:51])=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 5 (1.0 g), Pd(OAc)2 (9 mg), P(o-tolyl)3 (45.7 mg), methyl vinyl ketone (0.23 mL), and Et3N (0.78 mL) in 5.28 mL anhydrous DMF is heated in a sealed tube at 100° C. overnight. The reaction mixture is cooled to room temperature and then cooled in an ice bath. The cooled reaction mixture is poured into 20 mL ice cold 1N HCl. A brown solid precipitated and is collected. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 453.4 mg (52%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].O>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: COCC(=O)Cl
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)N(C)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.5 g, 1.69 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.19 g, 5.1 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 30 min then methoxyacetyl chloride (0.27 g, 2.5 mmol) was added dropwise and the reaction mixture was stirred at RT for 24 hours. After this time, water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 50% hexane, 50% EtOAc) gave the title compound (0.47 g, 76% yield) as a white solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:17]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[Na].O>C(O)C>[CH2:1]([CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]([O:25][CH2:26][CH3:27])=[O:24])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(=O)OCC
Yield: 59 %

Procedure:
Then, 501 g of farnesyl bromide as mentioned above and 285 g of diethyl malonate in 1,500 ml of ethanol were subjected to a condensation reaction in the presence of 37.1 g of metallic sodium. The reaction mixture was poured into water and extracted with ether. The organic layer was dried over anhydrous sodium sulfate. After removing the solvent, the residue was fractionated in vacuo to give 378 g of diethyl farnesylmalonate, b.p. 155° - 160° C. (0.2 mmHg). This product was saponified and decarboxylated in 1,000 ml of ethanol with 204 g of potassium hydroxide. The reaction mixture was neutralized with hydrochloric acid and extracted with ether. After removing the solvent, the residue was fractionated in vacuo to give 218 g of farnesylacetic acid, b.p. 142° - 150° C. (0.2 mmHg). The gas chromatographic analysis using 5% of polyethylene glycol 20 M (PGE-20M. for short) on kieselguhr (60- 80 mesh) at 180° C. of the column temperature, indicated that the substance was a mixture of stereo-isomers, 16% of Δ4,8 -cis-isomer, 48% of Δ4 -cis-Δ 8 -trans- and Δ4 -trans-Δ 8 -cis-isomers, and 36% of Δ4 -trans-Δ 8 -trans-isomer. By further fractionation through a rectifying column with 40 theoretical plates, was obtained 56.5 g of Δ4,8 -trans-farnesylacetic acid, b.p. 147° - 149° C. (0.2 mmHg). This showed that the Δ4,8 -trans-isomer was recovered in a yield of 72% based on the amount contained in the mixture. Subsequently, 150 g of farnesylacetic acid, which was obtained as the first distillate, was isomerized by heating with 0.15 g of acetylacetonatoruthenium RU (AA)3 at 200° C. in a nitrogenous atmosphere. By gas chromatographic analysis, the ratio of Δ4,8 -cis-isomer, Δ4 -cis-Δ 8 -trans-isomer+ Δ4 -trans-Δ 8 -cis-isomer and Δ4,8 -trans-isomer was 23.3:69.7:7.0 in the starting farnesylacetic acid and was 17.7:52.9:29.4 after isomerization.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:48][NH:49][C:50]([NH2:52])=[S:51]>C1COCC1.CN(C=O)C>[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:48][NH:49][C:50](=[S:51])[NH2:52])=[O:33])=[CH:35][CH:36]=2)=[CH:13][CH:12]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: NNC(N)=S
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)O)cc2)Cc2ccc(C#N)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)NNC(N)=S)cc2)Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.9 mg (0.05 mmol) of oxalyl chloride are slowly added dropwise to a solution of 12.7 mg (0.02 mmol) of 4-[(4E)-5-{2-[(4-tert-butylbenzyl)oxy]phenyl}-3-(4-cyanobenzyl)pent-4-en-1-yl]-benzoic acid from Example 100A in 0.2 ml of dry THF with 1 drop of DMF while cooling in ice. The reaction mixture is stirred at RT for 30 minutes and then concentrated in vacuo, and the residue is coevaporated twice with dichloromethane and then taken up in 0.2 ml of THF. This solution is added dropwise to a solution of 4.2 mg (0.05 mmol) of thiosemicarbazide in 0.25 ml of THF at 0° C. The mixture is stirred at RT for 1 hour and then concentrated, and the residue is reacted without further purification in the next stage.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:23]=[CH:22][C:8]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O>C(OCC)(=O)C>[O:25]=[C:24]1[N:4]([C:5]2[CH:6]=[CH:7][C:8]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:23]=2)[CH2:3][CH2:2][O:1]1
Reactant: CCOC(=O)C(=CNc1ccc(NCCO)cc1)C(=O)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(N2CCOC2=O)cc1)C(=O)OCC
Yield: 88.7 %

Procedure:
To a flask containing diethyl 2-({4-[(2-hydroxyethyl)amino]anilino}methylene)-malonate (0.48 g) and 1,1'-carbonyldiimidazole (0.32 g) is added toluene (15 mL). The reaction mixture is heated to reflux under an argon atmosphere overnight. The reaction mixture is cooled to room temperatue and partioned between ethyl acetate and phosphate buffer (pH=7, 1M). The phases are separated and the aqueous layer is extracted with two additional portions of ethyl acetate. The combined organic layers are washed with buffer, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica eluting with ethyl acetate. The product-containing fractions are evaporated to give 0.46 g of diethyl 2-{[4-(2-oxo-1,3-oxazolidin-3-yl)anilino]methylene}malonate as a creme solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>CN(C=O)C.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]>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COc1cc(F)cc(B(O)O)c1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Yield: 18.2 %

Procedure:
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.52 g, 5.82 mmol), 3-fluoro-5-methoxyphenylboronic acid (1.4 g, 8.24 mmol), Pd(dppf)Cl2 (0.18 g, 0.246 mmol) and 8.7 mL of 1M NaOHaqueous (8.73 mmol) were reacted in DMF (13 mL) under Ar at 120° C. for 48 hrs. The reaction was quenched by the addition of 1M HClaqueous (10 mL), dried under reduced pressure and the dark crude oil purified via flash chromatography on silica gel using a Biotage 100G SNAP with a gradient of DCM and iPrOH to give the title compound (275 mg, 18.2%) as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.ClCCN1CC[O:28]CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:28][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: ClCCN1CCOCC1
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Agent: Cl
Product: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1, Step A is replaced by an equimolecular quantity of N-(2-chloroethyl)morpholine hydrochloride. The product is obtained as a colorless oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH3:12]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O1CCOCC1>[NH2:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc2ccccc12
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cncc2ccccc12
Temperature: 165 °C
Reaction time: 21 h

Procedure:
A suspension of 4-bromoisoquinoline (25.0 g), copper(II) sulfate pentahydrate (30.4 g, Nacalai Tesque), 28% aqueous ammonia (100 ml) and 1,4-dioxane (100 ml) was stirred in a sealed tube at 165° C. for 21 hours. The reaction mixture was cooled to room temperature, the insoluble matters were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate (150 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (13.2 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([C:22]([CH3:28])([CH3:27])[C:23](OC)=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O1CCCC1.[BH4-].[Na+].CO>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([C:22]([CH3:28])([CH3:27])[CH2:23][OH:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C(C)(C)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CO)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Methyl 2-[6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]-2-methylpropanoate (0.299 g, 0.739 mmol) was dissolved in tetrahydrofuran (6 mL, 80 mmol). Sodium tetrahydroborate was then added (70. mg, 1.8 mmol), followed by methanol (450 μL, 11 mmol) in portions. The reaction mixture was stirred 30 min, at which point LCMS showed 50% conversion. After 2 h, LCMS showed no remaining ester, and showed the product (M+H 377), and several over-reduction by-products. The reaction was quenched with water, the solvent removed by rotary evaporation. Aqueous bicarbonate was added, and then EtOAc was added. The mixture was then stirred 0.5 h. The EtOAc layer was shaken with brine, dried (Na2SO4), and the solvent removed by rotary evaporation. The product was purified by automatic silica gel chromatography on a 40 g silica gel column, using solvent A=hexane; solvent B=2% iPA/EtOAc; flow 40 mL/min; A, 2 min; gradient to 30% B in 35 min; detector set at 254 nm; retention time, 26 min. The solvent was removed by rotary evaporation to yield 230 mg of a colorless viscous oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].O.ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:17]>C1(C)C=CC=CC=1>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:17])(=[O:4])=[O:3]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
300 g of 3-(chlorosulfonyl)benzoic acid containing 38.8% of water (corresponding to 183.6 g (0.83 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 100 g of water and heated to 100° C. for 1 hour. Then 500 g of toluene are added dropwise over 1 hour and a total of 164 ml of water distilled off azeotropically with toluene. The reaction mixture is cooled and the precipitated product filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 163.5 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 98.2%; this corresponds to a yield of 95.4%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[ClH:25].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][C:28]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)[CH:38]=1.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:57][CH2:56][CH2:55][CH2:54]1.CN(C=O)C>O>[ClH:25].[ClH:25].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:50][CH2:51][CH2:52][N:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[O:33])=[CH:29][C:28]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)[CH:38]=1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3F)ccn2)n1
Reactant: NCCN1CCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN4CCCC4)ccc3F)ccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A 3 dram vial was charged with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.488 g, 1.05 mmol), 4-fluoro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (Example 107; 0.200 g, 0.524 mmol), N-(2-aminoethyl)pyrrolidine (0.179 g, 1.57 mmol) and DMF (3 mL). The reaction was stirred for 1 hour at ambient temperature. Water was added and the reaction was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography. 2M HCl in ether was added to the isolated material and the collected solids were dried over high vacuum to give the title compound (0.078 g, 28.9% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.21 (bs, 1H), 9.75 (bs, 1H), 8.86 (t, 1H), 8.23 (m, 1H), 7.92 (m, 2H), 7.64 (dd, 1H), 6.62 (m, 2H), 6.58 (d, 1H), 3.60 (m, 4H), 3.32 (quart, 2H), 3.03 (m, 2H), 2.21 (d, 3H), 2.00 (d, 2H), 1.85 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22]>ClCCl>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[CH3:22]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a stirred solution of 2-trifluoromethylbenzenesulfonyl chloride (3.8 g) in dichloromethane (100 mL) under argon was added pyridine (14 mL). A solution of N-benzylglycine ethylester (2 g) in dichloromethane (40 mL) was added slowly. The mixture was stirred at r.t. overnight and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane to cyclohexane/ethyl acetate 1:1) to give [benzyl-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid ethyl ester (2.61 g) as a colorless oil. MS: 402.1 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:22]>>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[N:19]=[C:18]([NH2:22])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCOCC1
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCOCC1
Temperature: 120 °C
Yield: 74.3 %

Procedure:
6′-Bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4(3H)-thione (Example 25 Step 3, 415 mg, 1.14 mmol) was taken up in NH3 (7M in MeOH, 13 mL, 91 mmol) and the resulting mixture was heated in a microwave reactor at 120° C. for 2×1 h. The mixture was concentrated and the resulting residue was taken up in NH3 (7M in MeOH, 13 mL, 91 mmol) and then heated again for 1 h at 120° C. The mixture was concentrated and the resulting residue was taken up in DCM (10 mL) and sat. aq. NaHCO3 (5 mL) and poured into a phase separator. The organic layer was collected, concentrated and purified on a silica gel column eluted with 0-10% (0.1M NH3 in MeOH) in DCM to give 295 mg (75% yield) of the title compound: 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (dd, 1 H), 7.27 (d, 1 H), 6.68 (d, 1 H), 6.65 (br. s, 1 H), 3.65 (m, 2 H), 3.46 (m, 1 H), 3.38 (m, 1 H), 3.15 (m, 1 H), 3.00 (m, 1 H), 2.18 (s, 3 H), 1.66 (td, 1 H), 1.19 (m, 3 H); MS (ES+) m/z 348[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=S)[CH3:9])=[CH:4][CH:3]=1.[C:25]([NH:28][NH2:29])(=O)[CH3:26]>C(#N)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:25]([CH3:26])=[N:28][N:29]=[C:11]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)NN
Reactant: C[C@H](NC(=S)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CC#N
Product: Cc1nnc([C@H]2CCCN2C(=O)OC(C)(C)C)n1[C@@H](C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the product of Step B (1.7 g, 4.6 mmol) and acetic hydrazide (0.76 g, 9.2 mmol) in 30 ml acetonitile was added mercury (II) acetate (2.2 g, 6.9 mmol) and the mixture was stirred at room temperature for overnight. The mixture was filtered over a Celite-fritted funnel and washed with more acetonitrile. The filtrate was concentrated in vacuo. Run wash column yield the desired product containing minor impurities (1.3 g, 72%), was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:28](=[O:31])[CH:29]=[CH2:30])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)Cl
Reactant: Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reaction time: 8 h

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.3 g, 1.12 mmol) in dichloromethane (10 mL), triethylamine (0.19 mL, 1.34 mmol) and acryloyl chloride (0.11 mL, 1.23 mmol) were added successively and the mixture was stirred overnight. The reaction was hydrolysed, and the organic phase washed with water, dried over magnesium sulfate and concentrated under reduced pressure. A minimum amount of dichloromethane was added to the crude, diethylether was added and the resulting solid collected by filtration. LCMS Method: 2: RT: 4.23 min, 323 [M+1].
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:24]=[C:25](O)[CH:26]=1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[CH:24]=[C:25]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:26]=1)[CH3:17]
Reactant: CCOC(=O)Cc1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (570 mg, 2.0 mmol) was added drop wise to a solution of (5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (546 mg, 1.69 mmol) and pyridine (0.41 mL, 5.0 mmol) in DCM (10 mL) at 0° C. The temperature was maintained at 0° C. for 15 mins before warming to room temperature and the mixture stirred for 18 hrs. The reaction was diluted with DCM, washed with H2O, Na2CO3, dil. HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The residue was purified by flash column chromatography (EtOAc:petroleum ether), yield 695 mg (96%). 1H NMR (CDCl3) δ 7.72 (d, 2H), 7.66 (d, 2H), 7.54 (t, 1H), 7.39 (t, 1H), 7.28 (t, 1H), 4.19 (q, 2H), 3.73 (s, 2H), 1.28 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:15][CH3:16])[C:10](OCC)=[O:11])=[CH:5][CH:4]=1.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:15][CH3:16])[C:10]([NH:19][NH2:20])=[O:11])=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)C(OC)c1ccc(N(C)C)cc1
Solvent: CCO
Solvent: O
Product: COC(C(=O)NN)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 38.8 %

Procedure:
To a solution of ethyl 2-(4-(dimethylamino)phenyl)-2-methoxyacetate (0.675 g, 2.84 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (0.8 mL, 16.4 mmol) and the mixture was heated at reflux for 22 hours. Additional hydrazine hydrate (1.0 mL, 20.6 mmol) was added and the heating continued for 7 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The solid product was stirred with hot diethyl ether then hexanes were added. After cooling to room temperature, the solids were collected on a Büchner funnel and rinsed with 50% diethyl ether-hexanes then dried under vacuum to give 2-(4-(dimethylamino)phenyl)-2-methoxyacetohydrazide as an orange solid (0.246 g). Additional product was isolated from the mother liquor by chromatography (80-100% EtOAc-hexanes, then 5% methanol-EtOAc) to give an off-white solid (0.173 g, 66% yield total).