Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:7]=1.[Br:32][C:33]1[C:34](Cl)=[N:35][C:36]([Cl:39])=[N:37][CH:38]=1>>[Br:32][C:33]1[C:34]([NH:1][C:2]2[CH:3]=[C:4]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=3)[CH:5]=[C:6]([S:8]([NH:11][C:12]([CH3:14])([CH3:15])[CH3:13])(=[O:10])=[O:9])[CH:7]=2)=[N:35][C:36]([Cl:39])=[N:37][CH:38]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(N)cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Product: CC(C)(C)NS(=O)(=O)c1cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)cc(Nc2nc(Cl)ncc2Br)c1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example B5, step G using tert-butyl [3-(2-{3-amino-5-[(tert-butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate and 5-bromo-2,4-dichloropyrimidine as the starting materials in 44% yield. LCMS for C27H33BrClN5O4SNa (M+Na)+: m/z=660.3, 662.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(F)c21
Temperature: 90 °C
Yield: 75.3 %

Procedure:
A mixture of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.25 g, 1.0 mmol), cesium carbonate (0.65 g, 2.0 mmol) and 2-chloropyrazine (0.17 g, 1.5 mmol) in DMF (3 mL) was heated to 90° C. for 3 hr. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (EtOAc/PE=1/2) on silica gel to give the title compound as a light yellow solid (0.25 g, Yield: 76.7%). MS (ESI) m/z=333 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[CH2:25]([N:24]([CH2:27][CH3:28])[CH2:23][CH2:22][NH:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:37]3[CH:38]=[N:39][NH:40][CH:41]=3)=[CH:3][N:4]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19])[CH3:26]
Reactant: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cc1

Procedure:
In the same way as described for Compound 85, step 1, using 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)-N-(2-diethylaminoethyl)benzenesulfonamide (100 mg, 0.21 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (17 mg, 0.086 mmol), Pd(PPh3)4 (9 mg, 0.007 mmol) and NaOtBu (27 mg, 0.29 mmol) in DMF:water (3:1, 6 mL). The crude residue is chromatographed on silica gel, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH). The fractions containing the desired product are combined and evaporated, to afford the title compound as a yellow solid. HPLC (254 nm): Rt 2.04 min (97.2%); m/z (APCI) 455 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]=[C:17]=[S:18].N[C:20]1[C:21]([NH:41][CH3:42])=[N:22][C:23]([O:36][CH2:37][CH:38]([F:40])[F:39])=[C:24]([CH:35]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:26].CC#[N:45]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:16][C:17]([NH:45][C:23]1([O:36][CH2:37][CH:38]([F:40])[F:39])[C:24]([C:25](=[O:26])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)=[CH:35][CH:20]=[C:21]([NH:41][CH3:42])[NH:22]1)=[S:18]
Reactant: CNc1nc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CC#N
Product: CNC1=CC=C(C(=O)Nc2ccc(Br)cc2)C(NC(=S)Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)(OCC(F)F)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(4-Chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (66 mg, 0.23 mmol) is added to 5-amino-N-(4-bromo-phenyl)-2-(2,2-difluoro-ethoxy)-6-methylamino-nicotinamide (93 mg, 0.23 mmol) in MeCN (3.5 mL) and stirred at rt overnight. The reaction mixture is filtered and the filtercake is dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1C=CC=CC=1>[CH:12]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC(C)c1cc(Br)c2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(C)c1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1
Yield: 89.3 %

Procedure:
8-Bromo-6-isopropylquinoline (1.15 g) was dissolved in 46 mL of ethanol/benzene (1:1). 3-Nitrobenzene boronic acid (1.4 g), Na2CO3 (2M, 9.2 mL) and tetrakistriphenylphosphine palladium (0.23 g) were added successively. The reaction mixture was refluxed for 6 hours and then cooled and concentrated. The resulting residue was partitioned between 75 mL H2O and 100 mL of ethyl acetate, and extracted with ethyl acetate (2×100 mL). The extracts were then dried over MgSO4, filtered, concentrated and chromatographed on silica gel (20:80 ethyl acetate:hexane) yielding 1.2 g of 6-isopropyl-8-(3-nitrophenyl)quinoline as a slightly impure yellow oil.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[BH4-].[Na+].Cl>C(O)C.O>[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0° C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.57 mL, 52.4 mmol). The mixture is heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.77 (s, 2H) 7.09 (m, 1H) 7.19 (t, J=7.96 Hz, 1H) 7.38 (m, 1H); LC/MS: MS (ES+) m/e 257.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH:32]=O)[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:32][CH2:31][CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=CCCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CCCN)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A solution of 5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl ester (0.118 g, 0.5 mmol) and diisopropylethylamine (0.071 g, 0.55 mmol) in 10 mL MeOH was stirred at room temperature for 30 minutes and 3-(3-chloro-phenyl)-propionaldehyde (0.093 g, 0.55 mmol) was added. The mixture was stirred for 90 minutes. The reaction was cooled to 0° C., NaBH4 (0.83 mL, 5.98 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched with 1:1 NaHCO3:H2O and was washed with CH2Cl2. The CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an oil (171 mg). MS 352 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][OH:27])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CN1CCOCC1>[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][O:27][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reaction time: 4.5 h
Yield: 94.2 %

Procedure:
15.4 g of p-nitrobenzenesulphonyl chloride are added in portions at 20°-25° C. to a stirred suspension of 12.0 g of the alcohol from Example 8 in 35 ml of THF and 7.66 ml of N-methylmorpholine and stirred for 4.5 hours. The suspension is again treated with 0.77 ml of N-methylmorpholine and stirred at 22° C. for 4.5 hours. The mixture is treated with 70 ml of a 2% sodium bicarbonate solution, stirred for 1.5 hours, filtered, the residue is washed with water and ethanol and dried to give 21.4 g (94%) of 98.5 % p-nitrobenzenesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, m.p. 148°-149.5° C., [α]D20 : +10.0° (1% in acetone).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:26][CH:27]=1)[CH2:34][C:30]1[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=1
Reactant: Cn1ccnc1C=O
Reactant: CN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCN1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 112 %

Procedure:
The compound (116.3 mg) obtained in Example 44-6 was dissolved in methanol (5.81 ml) and added with 1-methyl-2-imidazole carboxaldehyde (52.0 mg) and sodium cyanoborohydride (39.6 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 6 days. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution, and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (163.4 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)([OH:7])=[O:6].N>[NH2-].[Na+]>[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:2]([CH3:3])[C:1]#[N:4])=[CH:14][CH:13]=1)([OH:7])=[O:6]
Reactant: CCC#N
Reactant: O=C(O)c1ccccc1CCc1ccc(Cl)cc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: CC(C#N)c1ccc(CCc2ccccc2C(=O)O)cc1
Yield: 43.9 %

Procedure:
Propionitrile (286.5 g.) is added over the course of 40 minutes and with vigorous stirring to a suspension of sodamide (248 g.) [prepared from sodium (139.5 g.) and liquid ammonia (4 litres)] and then 4-(2-carboxyphenethyl)chlorobenzene (117 g.) is added over the course of 10 minutes. The ammonia is allowed to evaporate during a period of 16 hours. The brown residue is taken up in anaesthetic grade diethyl ether (1 litre) and then in water (2 litres) with care. The alkaline aqueous solution is decanted, extracted with diethyl ether (2 × 400 cc.) and then acidified by adding sulphuric acid (d = 1.36; 350 cc.) whilst cooling. The oil which separates out is extracted with methylene chloride (2 × 500 cc.). The organic extracts are dried over anhydrous sodium sulphate (100 g.) and concentrated to dryness under reduced pressure (20 mm.Hg) at 60°C. The residual oil is dissolved in hot disopropyl ether (120 cc.); on cooling, a product crystallises and is filtered off. 2-[4-(2-Carboxyphenethyl)phenyl]propionitrile (55 g.), melting at 73°C., is thus obtained; after three recrystallisations from ethyl acetate, the product melts at 129°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][CH2:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1.C[Si](C)(C)[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[F-].[Cs+].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:11]1[CH:10]=[C:9]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[N:8]=[C:7]([CH2:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1
Reactant: C[Si](C)(C)n1ccnc1
Reactant: Clc1cccc(CCc2nc(Cl)cc(Cl)n2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1cccc(CCc2nc(Cl)cc(-n3ccnc3)n2)c1
Yield: 62.7 %

Procedure:
A solution of 2-(3-chlorophenethyl)-4,6-dichloropyrimidine (286 mg, 1 mmol) 91 in 3 mL of dry DMF was treated with 1-trimethylsilylimidazole (140 mg, 1 mmol) and CsF (152 mg, 1 mmol) at RT overnight. Aqueous work up and chromatography (silica gel, hexane:ethyl acetate, 1:1) gave 200 mg of 4-chloro-2-(3-chlorophenethyl)-6-(1-imidazolyl)pyrimidine (92).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].C([Li])CCC.CCCCCC.Cl[CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>O1CCCC1.CCOCC>[CH3:1][N:2]([CH3:9])[C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1
Reactant: CC(=O)CC(=O)N(C)C
Reactant: ClCc1ccsc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C(=O)CC(=O)CCc1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
N,N-Dimethyl acetoacetamide (46.8 g; 0.363 mole) was converted to its dianion by treatment with 80% sodium hydride (11.8 g; 0.393 mole) in dry tetrahydrofuran (350 ml) under nitrogen, at 20° C. The resulting suspension was diluted with dry ether (1 L) and stirred mechanically for 15 minutes at 0° C. before a solution of n-butyl lithium in hexane (227 ml; 1.6 M; 0.363 mole) was added dropwise. To the now clear mixture was then added 3-chloromethyl thiophene (38 g; 0.287 mole) in dry tetrahydrofuran (50 ml), again dropwise, and the reaction allowed to warm up to room temperature. After the solution had stood at room temperature overnight the solvents were removed on a rotary evaporator and the residue acidified with dilute HCl in the presence of ethyl acetate (200 ml). The organic layer was separated off and the aqueous layer extracted once again with ethyl acetate (200 ml). The combined organic layers were dried (anhydrous MgSO4), and evaporated to give an oil which was purified on a short silica gel column using chloroform as eluant affording the product as a red-brown oil (48.5 g; 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].S([O-])([O-])(=O)=O.[NH4+].[NH4+].[C:24](OCC)(=O)[CH3:25].[CH2:30]1COCC1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:24]([CH3:25])[O:10][C:9]([CH3:30])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: CC1Nc2ccc(Br)cc2C(C)(c2ccccc2)O1
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of (2-amino-5-bromophenyl)(phenyl)methanone (1 g, 3.6 mmol) in anhydrous THF (15 mL) was added at room temperature under nitrogen methylmagnesium bromide (3M in ether, 3 mL, 9 mmol). After 3 hours, the mixture was treated with a saturated aqueous ammonium sulfate solution (30 mL) and ethyl acetate (50 mL). The organic layer was separated, dried (MgSO4), and evaporated. The residue was then dissolved in anhydrous toluene and treated at ambient temperature under nitrogen with acetylaldehyde (2 mL). After 2 minutes, the solvent was removed and residue was purified by a column chromatography (silica gel, hexane:ethyl acetate/4:1) to afford 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine as a yellowish solid (0.8 g, 70%): MS (ESI) m/z 318/320 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33].CCN(CC)CC.Cl>O1CCOCC1>[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[S:32]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1)(=[O:34])=[O:33]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=c1[nH]c2nccc(Oc3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)c2c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Compound 137 (50 mg, 0.16 mmol), 2,3-dichloro-benzenesulfonyl chloride (45 mg, 0.18 mmol), and Et3N (0.07 mL, 0.49 mmol) were suspended in dioxane (2 mL), and stirred overnight at 80° C. The reaction mixture was acidified with 1M HCl, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 25 to 100% EtOAc in hexanes to provide 173 (14 mg, 17% yield) as a white solid. LC-MS (M+H=512, obsd.=512).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([O:13][C@H](C1C=CC=CC=1)C)=[O:12]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([OH:13])=[O:12]
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1F)N(C)C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@@H](C(=O)O)c1ccccc1F
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A mixture of (R)—((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)2/C (0.125 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H2 balloon) for 4 hours. The solution was then purged with Ar, filtered through diatomaceous earth (CELITE®), and concentrated in vacuo. This gave the title compound as a colorless solid (0.503 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86 (s, 6H). LCMS: Anal. Calcd. for C10H12FNO2: 197. Found: 198 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:6][O:5][CH:4]=[CH:3][CH2:2]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[Br:22][C:23]1[C:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:39][OH:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:22][C:23]1[C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:39][O:40][CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][O:5]1
Reactant: C1=COCCC1
Reactant: COc1ccc(COc2cccc(CO)c2Br)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COc2cccc(COC3CCCCO3)c2Br)cc1
Temperature: 25 °C

Procedure:
DHP (0.67 mL, 7.4 mmol) and CSA (30 mg, 0.12 mmol) were added to a solution of [2-bromo-3-(4-methoxy-benzyloxy)-phenyl]-methanol (2.0 g, 6.1 mmol) in CH2Cl2 (15 mL). The resulting mixture was stirred at rt O/N. 4 Å Molecular sieves (1.0 g) was added and mixture was stirred for 1 h. Sat. NaHCO3 was added and mixture was extracted with CHCl3 (2×50 mL). The organic fractions were washed with H2O (2×25 mL) then brine (50 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (25% EtOAc in hexane) to give the title compound as yellow oil: yield 1.30 g (96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[C:5](/[O:22][CH2:23][CH3:24])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH3:21])[CH3:2].B(F)(F)F.O(CC)CC.CSC>ClCCl>[CH2:1]([O:3][C:4](=[O:25])/[C:5](/[O:22][CH2:23][CH3:24])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1C)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CSC
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(O)cc1C)OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (Z)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-acrylic acid ethyl ester (46.1 g, 135.4 mmol) in dichloromethane (500 ml) was added BF3-OEt2 (186 ml, 677 mmol, 46%) and dimethyl sulfide (149 ml, 2.03 mol). The reaction mixture was stirred at ambient temperature for 14 h, poured onto ice water and extracted two times with dichloromethane. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/AcOEt) to give 23.1 g (92.3 mmol, 68% over three steps) of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CC#N>[N:11]1([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: N#Cc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of 4-cyanobenzylbromide (1.0 g, 5.1 mmol) in MeCN (10 ml) was added morpholine (0.44 g, 0.44 ml, 5.1 mmol) and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and partioned between CH2Cl2 and NaOH (2M). The organic layer was separated, dried over MgSO4 and dried to give the desired nitrile (0.70 g, 68%).