Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[O-:38][C:39]#[N:40].[Na+]>CC(O)=O.O>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:39]([NH2:40])=[O:38])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.5 %

Procedure:
To a solution of compound 126 (3.0 g, 5.72 mmol) in AcOH (13.6 mL) at 0° C. was added a solution of sodium cyanate (0.743 g, 11.44 mmol, 2 eq.) in water (5.2 mL). The mixture was stirred at r.t. for 20 h. Water (100 mL) was added and the reaction mixture turned into a suspension. After 30 min, the solid was collected by filtration and the product cake was washed with water (2×20 mL), dried in vacuum and purified by Biotage SPI Flash Purification System (eluent a gradient EA/MeOH, 100/0 to 90/10) to afford 288 as a white solid (2.0 g, 3.52 mmol, 62% yield). MS (m/z): 568.4 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[C:31]([N:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=2)[CH2:36][CH2:35]1)(=O)[CH3:32]>>[CH2:1]([N:3]([CH2:45][C:44]1[CH:43]=[CH:42][C:41]([O:40][CH:37]2[CH2:38][CH2:39][N:34]([CH2:31][CH3:32])[CH2:35][CH2:36]2)=[CH:48][CH:47]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN1CCC(Oc2ccc(CN(CC)c3cc(OC)c(OC)cc3[C@@H]3CCc4cc(O)ccc4C3)cc2)CC1
Yield: 49.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(1-acetylpiperidin-4-yloxy)benzaldehyde (57 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:38]1[CH:52]=[CH:51][C:41]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])=[CH:40][C:39]=1[F:53]>>[CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:38]4[CH:52]=[CH:51][C:41]([CH2:42][O:43][Si:44]([C:47]([CH3:49])([CH3:48])[CH3:50])([CH3:45])[CH3:46])=[CH:40][C:39]=4[F:53])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)c(F)c1
Reactant: Cc1nc(CC2CCN(c3ccc(Br)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO[Si](C)(C)C(C)(C)C)cc4F)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Yield: 16 %

Procedure:
In accordance with Example 19-(2), but using tert-butyl 5-(benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and [(4-bromo-3-fluorobenzyl)oxy](tert-butyl)dimethylsilane instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 16%) was afforded as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][SH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].II>C(Cl)Cl.C(N(CC)CC)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:9][S:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CSSCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
1.0 g of p-nitrobenzylmercaptan was dissolved in 30 of methylene chloride and 0.83 ml of triethylamine and 750 mg of iodine were added while maintaining the temperature at 25° C. and stirring for 10 minutes. After washing with N hydrochloric acid, the organic phase was dried and the solvent was evaporated. 20 ml of ether were added to the residue, and after stirring for 10 minutes, separating and drying, 839 mg of p-nitrobenzyl disulfide melting at 126° C. were obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73])=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycine (12.8 mg, 0.023 mmol) in DMF (2 ml) was added N-methylmorpholine (15 μl, 0.091 mmol). TBTU (8.8 mg, 0.027 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. D-valine (4.5 mg, 0.038 mmol) was added and the mixture was stirred at ambient temperature overnight. The solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 0.80 (bs, 6H), 1.92-2.04 (m, 1H), 2.77-2.90 (m, 2H), 3.77 (bs, 2H), 3.94-4.10 (b, 1H), 4.22-4.30 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 4.99-5.03 (m, 1H), 5.90-5.94 (m, 2H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.09-7.15 (m, 2H), 7.18-7.24 (m, 2H), 7.34 (d, 2H), 8.23 (bs, 1H). M/z: 666.67 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:18]([Cl:17])[CH:19]=2)[N:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(3,4-dichlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4-dichlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([CH3:24])([C:16](=[O:23])[NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH3:15])[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][C:14]([C:16](=[O:23])[NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)([O:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:25])=[O:5])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1cccc(OC(C)(C)C(=O)Nc2nccs2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Oc1cccc(C(=O)O)c1)C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 3-[1-Methyl-1-(thiazol-2-ylcarbamoyl)-ethoxy]-benzoic acid tert-butyl ester (0.1 g, 0.275 mmol) in DCM (2 ml) a solution of TFA (3 ml) in DCM (3 ml) was added at 0° C. for 15 min. Reaction mixture was stirred at RT for 1 h, diluted with DCM (10 ml) washed with brine (2×4 ml) dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was triturated with hexane to obtain white solid, filtered and dried to obtain 3-[1-Methyl-1-(thiazol-2-ylcarbamoyl)-ethoxy]-benzoic acid (0.06 g, 85%). 3-[1-Methyl-1-(thiazol-2-ylcarbamoyl)-ethoxy]-benzoic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([C:4]2[N:3]=[C:2]([NH:33][C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[C:7]([C:8]#[N:9])=[CH:6][N:5]=2)=[N:11]1
Reactant: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Cl
Reactant: Nc1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1

Procedure:
73 mg of 4-chloro-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidine-5-carbonitrile (1-14-1, 0.201 mmol, 1. eq.), 22.66 mg of pyridin-4-amine (0.241 mmol, 1.2 eq.), 42 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.241 mmol, 1.2 eq.) and 1 ml of N,N-dimethylformamide were stirred at room temperature for 24 hours. The reaction mixture was partitioned between half-saturated aqueous sodium hydrogen carbonate solution and dichloromethane/isopropanol 4:1. The aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC to yield 24.4 mg (0.06 mmol, 28.9%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:7][C:6]=1Br.CCCCCC.C([Li])CCC.CN([CH:31]=[O:32])C>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](=[CH:7][C:8]([CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=1)[CH:31]=[O:32]
Reactant: COCOCc1ccc(OCOC)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOCc1ccc(OCOC)c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-4-methoxymethoxymethylphenol methoxymethyl ether (11.18 g) in diethyl ether (400 ml) was cooled to -78° C. To the solution was added dropwise a 1.6M n-butyl lithium hexane solution (28 ml) under argon atmosphere. The mixture was stirred for one hour while maintaining the temperature, to which was added dropwise DMF (5 ml), followed by raising the temperature up to room temperature and stirring overnight. The reaction mixture was subjected to extraction with the addition of water and ethyl acetate. The organic layer was washed (a saturated aqueous saline solution) and dried (anhydrous magnesium sulfate). Then, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-methoxymethoxymethyl salicylaldehyde methoxymethyl ether (7.23 g) (Compound B-23). The physical properties are shown in Table 7.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:30][CH2:31][CH2:32][C:33]#[N:34]>CC(C)CC(=O)C>[C:33]([CH2:32][CH2:31][CH2:30][N:12]1[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11]1)#[N:34]
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: N#CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The starting material for said product No. (4) is prepared as follows. The mixture of 4.63 g of 4-diphenylmethoxypiperidine, 4.63 g of anhydrous sodium carbonate, 0.3 g of sodium iodide, 1.81 g of 4-chlorobutyronitrile and 60 ml of 4-methyl-2-pentanone is stirred and refluxed for 22 hours. It is evaporated, the residue taken up in diethyl ether, the solution washed with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated, to give the 1-(3-cyanopropyl)-4-diphenylmethoxypiperidine, which is sufficiently pure to be used directly for the reduction to the 1-(4-aminobutyl)-4-diphenylmethoxypiperidine previously described.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccccc4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes, and benzoyl chloride (0.4 g, 3.2 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was stirred with 2N HCl (30 mL) and CH2Cl2 (80 mL). The solid was collected to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.5 g, 68%) as a white solid: mp 228-230° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.48 (d, J=17.3 Hz, 1H), 4.53 (d, J=22.1 Hz, 1H), 4.55 (s, 2H), 5.12-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.44-7.65 (m, 6H, Ar), 7.87 (d, J=7.1 Hz, 2H, Ar), 9.11 (t, J=5.7 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.61, 31.20, 46.30, 51.60, 121.67, 127.25, 128.35, 130.67, 131.36, 131.63, 134.07, 134.74, 140.16, 166.37, 168.10, 171.04, 172.88; Anal. calcd. for C21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.58; H, 5.08; N, 11.12.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:14])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](O)Cc1ccccc1
Yield: 98 %

Procedure:
A solution of commercially available (S)-2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1g) in methanol (125 mL) was refluxed with removal of water using 3A molecular sieves for 17 h. The solution was concentrated and dissolved in ether. The ether solution was washed with saturated sodium bicarbonate, brine and concentrated to provide the title compound as a white solid (5.32 g, 98%): NMR (CDCl3): δ 7.36-7.20 (m, 5H), 4.47 (ddd, J=5, 6, 7 Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5, 14 Hz, 1H), 2.97 (dd, J=7, 14 Hz), 2.69 (d, J=6 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-])=O)=[N:3]1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1cn(C)nc1Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C)nc1Nc1ccc(C(F)(F)F)cc1N

Procedure:
Ethyl 1-methyl-3-(2-nitro-4-trifluoromethylanilino)pyrazole-4-carboxylate (9.2 g) was hydrogenated at 60 p.s.i. in a mixture of ethyl acetate (200 ml) and ethanol (50 ml) over 10% palladium on charcoal (1.0 g). The catalyst was removed by filtration, the solvent evaporated and the residue crystallised from carbon tetrachloride to give the title compound m.p. 162° C.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]1([CH2:21][C:22]([Cl:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:24].[C:9]1([N:6]2[CH:7]=[CH:8][C:3](=[N:2][C:22](=[O:23])[CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[N:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Product: O=C(Cc1ccccc1)N=c1ccn(-c2ccccc2)nc1
Yield: 41 %

Procedure:
6.0 g (28.9 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 50 ml of phenylacetyl chloride were kept at 120° C. for 6 hours, while stirring. The mixture was cooled and then evaporated down, and the residue was treated with methanol/methyl tert.-butyl ether. The solid was filtered off under suction and recrystallized first from ethanol and then from ethanol/acetone with the addition of active charcoal. 3.9 g (41% of theory) of 1,4-dihydro-1-phenyl-4-[(phenylacetyl)-imino]-pyridazine hydrochloride were isolated as pale beige crystals of melting point 208°-210° C.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: c1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: -78 °C

Procedure:
n-Butyllithium (1.6M, 5.3 mL, 8.37 mmol) was added to a solution of thiazole (450 mg, 5.23 mmol) in anhydrous ether (30 mL) stirred −78° C. under nitrogen. After 30 min tri-n-butylstannyl chloride (2.73 g, 8.37 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound a brown oily residue (2.0 g), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(C3C4C(=CC=CC=4)C(C4C=CC5OCOC=5C=4)=C3C(OCC)=O)=CC=2O1>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Solvent: CO
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Ethyl (1RS, 3RS)-1,3-Di-(3,4-methylenedioxy-phenyl)indane-2-carboxylate. Ethyl (RS)-1,3-di-(3,4-Methylenedioxyphenyl)indene-2-carboxylate (163 mg, 0.38 mmol) was placed in MeOH (0.05 ml), and to this was added SmI2 (10 ml of 0.1M solution in THF, 1.0 mmol). The resulting mixture was stirred under an argon atmosphere overnight, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional SmI2 (5 ml of 0.1M solution in THF, 0.5 mmol) was added, and stirring was continued for 2 h. The reaction mixture was partitioned between Et2O and 5% aqueous Na2S2O3. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a colorless, glassy solid (120 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br-:12].[Br-:13].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.O>[Br:12][C:6]1([Br:13])[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: [Br-]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1Nc2cc(Cl)ccc2C1(Br)Br
Reaction time: 3.5 h
Yield: 101.2 %

Procedure:
At room temperature, to a solution of 6-chlorooxindole (10.0 g, 59.7 mmol ) in t-BuOH (500 mL) and water (2.6 mL) was added pyridinium tribromide (57.25 g, 79 mmol, 3 eq) and the reaction was stirred for 3.5 hr. The reaction was diluted with water (500 mL) and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaHCO3 (3×), dried over MgSO4, filtered and concentrated to give the title compound as a tan solid (19.66 g, 100% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 325 [M+H].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:39])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[O:26]1.CS(C)=O>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([B:27]4[O:28][C:29]([CH3:31])([CH3:30])[C:25]([CH3:39])([CH3:24])[O:26]4)=[CH:38][CH:37]=3)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 23 %

Procedure:
A 18-mL vial was charged with [2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (39 mg, 0.1 mmole) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22 mg, 0.1 mmol) and DMSO (0.5 ml). The resulting mixture was stirred under Ar for 3.5 hr. After cooling to room temperature, water was added to the mixture (5 ml). The precipitate was collected by filtration and the crude product was purified by chromatography on silica gel using hexane/DCM (4:1) followed by 2% of methanol in DCM as eluent to afford the title compound, containing impurities, which was forward to the next step without any further purification (10.3 mg, 23% yield).