Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=NC=1.CS([C:11]1[N:12]=[C:13]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:28][CH2:27]2)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][O:17][C:15]=2[N:16]=1)(=O)=O.[BH4-].[Na+]>C(O)C>[C:20]1([C:19]2[C:14]3[C:13]([N:26]4[CH2:31][CH2:30][CH:29]([CH2:32][O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][CH2:39][CH2:40]5)[CH2:28][CH2:27]4)=[N:12][CH:11]=[N:16][C:15]=3[O:17][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)c1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)coc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1cncnc1
Product: c1ccc(-c2coc3ncnc(N4CCC(COCCN5CCCC5)CC4)c23)cc1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
2-Methylsulphonyl-5-phenyl-4 [4-2-pyrrolidin-1-ylethoxymethyl-1-piperidyl]furo[2,3-d]-pyrimidine pyrimidine (75 mg, 0.15 mmol) in ethanol (5.0 mL) was treated with sodium borohydride (15 mg, 0.38 mmol) at 20° C. with continuous stirring for 30 min. A further 30 mg of sodium borohydride was added and the reaction was stirred at 20° C. for a further 1 h. A further 60 mg of sodium borohydride was added and the reaction was stirred at 20° C. for a further 1 hr then concentrated in vacuum to a gum and the residue partitioned between dichloromethane and water. The dichloromethane layer was separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was purified by preparative HPLC to give 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]furo[2,3-d]pyrimidine (53 mg, 0.13 mmol, 84%). 1H NMR (CDCl3) δ: 1.02 (2H, m), 1.5 (2H, m), 1.75 (6H, m), 2.45-2.8 (9H, m), 3.2 (2H, d, J=8 Hz), 3.5 (2H, t, J=8 Hz), 3.95 (2H, d, J=12 Hz), 7.35-7.45 (5H, m), 7.52 (1H, s), 8.45 (1H, s). LCMS RT=5.14 min. M+1=407.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:26])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:25])[C:22]([NH2:24])=[O:23])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.[CH3:36][C:37](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:38].Cl.C1C[O:64][CH2:63][CH2:62]1>>[C:37]([NH:25][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:3]2[CH:4]=[C:5]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:7][C:2]=2[NH:1][C:63](=[O:64])[CH3:62])=[O:26])=[CH:16][CH:17]=1)[C:22]([NH2:24])=[O:23])(=[O:38])[CH3:36]
Reactant: C1CCOC1
Reactant: NC(=O)C(N)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C(NC(C)=O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[2-amino-5-(2-thienyl)phenyl]-4-(1,2-diamino-2-oxoethyl)benzamide (51 mg, 0.086 mmol) and DIPEA (52.4 μL, 0.300 mmol) were suspended in THF (1 mL) and acetic anyhdride (13 μL, 0.138 mmol) was added. The mixture was stirred at room temperature overnight. 2N HCl was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a blue-green solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.89 (s, 1H), 9.71 (s, 1H), 8.55 (d, J=7.8 Hz, 1H), 7.91 (m, 3H), 7.75 (s, 1H), 7.55 (m, 3H), 7.51 (d, J=5.4 Hz, 1H), 7.49 (m, 1H), 7.44 (m, 1H), 7.19 (s, 1H), 7.11 (m, 1H), 5.48 (d, J=7.8 Hz, 1H), 2.07 (s, 3H), 1.89 (s, 3H). MS: cal'd 451 (MH+), exp 451 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cn1ccc2ccc(C=O)cc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2ccn(C)c2c1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
1-Methyl-1H-indole-6-carbaldehyde (146 mg, 0.91 mmol) was dissolved in anhydrous methanol (4 ml). Methylamine (0.35 ml of 33% solution in ethanol, 2.81 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (4 ml). Sodium borohydride (34.9 mg, 0.92 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford methyl-(1-methyl-1H-indol-6-ylmethyl)-amine (139 mg, 87%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.240 (d, J=3.6, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.345 (d, J=4.0 Hz, 1H)), 3.75 (s, 3H), 3.73 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Reactant: CCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(CC)CNCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
To 4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (0.18 g, 0.56 mmol) in DMF (3 mL) was added 1-bromo-2-ethyl-butane (0.083 mL, 0.59 mmol) and potassium carbonate (0.093 g, 0.68 mmol). The reaction was allowed to stir at room temperature for 18 h. The reaction mixture was then diluted with EtOAc (30 mL) and H2O (30 mL). The organic phase was dried with sodium sulfate and concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 3% (2M NH3 in MeOH) in MeCl2) yielding 0.13 g (59%) pure product.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:7]=[N-:8]>C(#N)C.[Cu](I)I.C(N(CC)CC)C>[CH:1]1([C:4]2[N:8]=[N:7][N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#CC1CC1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)Cn1cc(C2CC2)nn1
Yield: 95.4 %

Procedure:
Cyclopropylacetylene (15 g, 0.116 mol), ethyl azidoacetate (11.5 g, 0.174 mol), triethylamine (0.32 mL, 2.33 mmol) and copper iodide (442 mg, 2.33 mmol) in acetonitrile (100 mL) were stirred at 25° C. for 18 hours. The mixture was evaporated in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography eluting with EtOAc: Hexane 40: 60 to afford the title compound as a colorless liquid (95%, 21.6 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:8]2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:50][NH:51][OH:52]>CN(C=O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:51]([OH:52])[CH3:50])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(COCCN3CCCC3=O)cn(Cc3ccc(F)cc3)c2cn1
Reactant: CNO
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(O)C(=O)c1cc2c(COCCN3CCCC3=O)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a stirring solution of 1-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (0.817 g, 1.99 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.418 g, 2.38 mmol) in DMF (20 mL) was added N-methyl morpholine (0.2409, 2.38 mmol). After stirring at room temperature for 2 hours, N-methyl hydroxylamine hydrochloride (1.66 g, 19.9 mmol) was added. The reaction stirred for 16 hours at room temperature. After stirring for 16 hours, the reaction was concentrated in vacuo yielding a yellow oil. The oily residue was partitioned between a saturated sodium bicarbonate solution and ethyl acetate (50:50, 50 mL: 50 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The organic phases were combined, washed with brine (100 mL), and dried over Na2SO4. The solution was filtered, concentrated, and triturated with diethyl ether to yield a pale yellow solid. The solid was recrystalized from isopropyl alcohol to give 1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-{[2-(2-oxopyrrolidin-1-yl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as clear needles (0.425 g, 49% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.76-1.85 (m, 2H) 2.13 (t, J=8.08 Hz, 2H) 3.26-3.35 (m, 8H) 3.51 (t, J=5.43 Hz, 2H) 4.65 (s, 2H) 5.54 (s, 2H) 7.16 (t, J=8.84 Hz, 2H) 7.36 (dd, J=8.59, 5.56 Hz, 2H) 7.86 (s, 1H) 8.01 (s, 1H) 8.89 (s, 1H)
Reaction SMILES: [Br:1][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:1].[C:26]1([P+:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]([CH3:12])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Solvent: CC#N
Product: CC(C(=O)c1ccc(Cl)cc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 66 %

Procedure:
The 2-bromo-4'-chloropropiophenone (58.1 g), which had been prepared in Example 5, and triphenyl phosphine (61.6 g) were dissolved in 250 ml of acetonitrile. The resulting solution was heated under reflex for 1.5 hours. After the completion of the reaction, the reaction mixture was cooled with ice, and the crystalline material thus formed was separated by filtration, washed with cold acetonitrile and dried in air to give triphenyl[1-(4-chlorophenyl)-1-oxo-2-propyl]-phosphonium bromide (79.0 g). mp 258°-258.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1.CN(C)C(=O)C.C(Cl)([Cl:20])=O>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([Cl:20])=[O:11])=[C:6]([CH3:8])[N:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1nc(C)c(C(=O)O)s1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1nc(C)c(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 10.4 g (0.06 mole) of 2-methoxy-4-methylthiazole-5carboxylic acid were suspended in 150 ml of tetrahydrofuran, followed by the addition of 0.02 g of N,N-dimethyl-acetamide. Under heating and reflux, phosgene was blown at a rate of 1.1 l/hr for 4.5 hours (0.23 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.8 g of 2-methoxy-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 96.2% and 93.9%, respectively.
Reaction SMILES: C(O)C.[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19](Br)([CH3:21])[CH3:20])#[N:14]>C1(C)C=CC=CC=1>[C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([O:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)([CH3:21])[CH3:20])#[N:14]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(Br)C(=O)NCCC#N
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)NCCC#N

Procedure:
Into a 25 liter reactor fitted with cooling and stirring means there were poured 3 liters of ethanol, 60 g of sodium and 250 g of p-chlorophenol (1.944 mol). After stirring for 1 hour there were added 3 liters of toluene and the ethanol/toluene azeotrope was removed by distillation; 2 more liters of toluene were added and also 425 g of N-cyanoethyl α -bromo-isobutyramide, (1.944 mol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][NH:28][C:19]([C@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH2:14]1)=[O:20]
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), by condensing (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent there is obtained (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=343 (M+H)+; [α]589=+28.17° (c=0.831, CH2Cl2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:14]([O-])([O-])=O.[K+].[K+].BrCC(O[CH2:25][CH3:26])=O>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:25]([CH3:26])[CH3:14])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 189.5 %

Procedure:
To a solution of compound 3 (2.66 g, 7.27 mmol) in DMF (15 mL) was added K2CO3 (2.00 g, 15 mmol) and ethyl bromoacetate (1.61 mL, 14.5 mmol). The resulting mixture was stirred at 60° C. for three hours. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. Purification with column chromatography (hexanes/EtOAc 50:50) gave the product 4 (3.02 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccnc(Cl)n2)CC1

Procedure:
2.0 g (13.4 mmol) of 2,4-dichloropyrimidine, 2.32 g (14.7 mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine were stirred in 20 ml of DMF at 50° C. for 4 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][C:12]=3[CH:25]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Yield: 6774.2 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Example 26, 1.35 g, 3.1 mmol) in ethyl acetate (30 mL) was added 5% palladium on carbon (wet). The resulting suspension was subjected to an atmosphere of hydrogen (40 psi) for 15 h. The catalyst was then removed by filtration through celite. The filtrate was concentrated to provide 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (748 mg, 210 mmol, 68% yield) as an orange viscous syrup. MS (EI) for C20H25N3O3: 356 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:20][C:16]1[CH:15]=[C:14]([C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2]([C:21]#[N:22])=[CH:11][C:10]=2[CH:12]=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cc(Br)c2cccnc2c1-c1cccc(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C=O)c(-c2cccc(F)c2)c2ncccc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 5-bromo-8-(3-fluorophenyl)quinoline-7-carbaldehyde (0.049 g, 0.15 mmol), zinc cyanide (0.035 g, 0.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.034 g, 0.030 mmol) in dry N,N-dimethylformamide (0.50 mL) was stirred at 130° C. overnight. The mixture was filtered, diluted with water, extracted with ethyl acetate. The combined extracts were dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 60% ethyl acetate in hexane) to give the desired product (20 mg, 50%). LCMS calculated for C17H10FN2O (M+H)+: m/z=277.1; Found: 277.0.
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1([S:9][S:10][CH:11]2[CH2:13][CH2:12]2)[CH2:8][CH2:7]1.Br[CH2:15][C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1.[Cl-].[NH4+]>C1COCC1>[CH3:21][C:18]1([CH3:22])[O:17][C@@H:16]([CH2:15][C:6]2([S:9][S:10][C:11]3([CH2:15][C@H:16]4[CH2:20][O:19][C:3]([CH3:4])([CH3:2])[O:17]4)[CH2:13][CH2:12]3)[CH2:8][CH2:7]2)[CH2:20][O:19]1
Reactant: C1CC1SSC1CC1
Reactant: [Li]CCCC
Reactant: CC1(C)OC[C@H](CBr)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CC2(SSC3(C[C@H]4COC(C)(C)O4)CC3)CC2)O1
Reaction time: 4 h

Procedure:
n-Butyl lithium (1.7 M in hexane, 1.2 eq) is added dropwise over 1 hour to a solution of 1,2-dicyclopropyldisulfane (1 eq) in THF (1.5 mL/mmol), at −20° C. (R)-4-(Bromomethyl)-2,2-dimethyl-1,3-dioxolane (1.1 eq) is then added at −78° C. and stiffing at −78° C. continued for an additional 4 hours. Saturated aqueous ammonium chloride solution is added and the mixture is extracted with ethyl acetate (3×). The combined organic extracts are dried (Na2SO4) and purified by flash chromatography (ethyl acetate in hexane eluant).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][N:37]2C(=O)C3=CC=CC=C3C2=O)=[O:10])=[CH:5][CH:4]=1.O.NN>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][NH2:37])=[O:10])=[CH:48][CH:49]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)cc1
Yield: 77.8 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-phthalimidomethyl-4-tritylthiopyrrolidine (752 mg: 1.124 mmole) in a mixture of dichloromethane (3 ml) and methanol (12 ml), hydrazine hydrate (109 μl: 2 eq.) is added. The mixture is heated for 5 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in dichloromethane (5 ml) and the solid is filtered off. The filtrate is washed with water and concentrated in vacuo. The residue is recrystallized from a mixture of dichloromethane and methanol to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine (471 mg). Yield: 78%. mp. 165° to 167° C. NMR δ(CDCl3 :CD3OD=2:1) ppm: 3.46(s, 3H), 4.96, 4.89(ABq, J=12 Hz, 2H). IR ν (CHCl3) cm-1 : 1683, 1610.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)O1.I[C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[N:26][C:27]=4[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=3)=[CH:17][C:13]=2[CH:14]=[CH:15]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3occc3c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 64.8 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (56 mg, 0.23 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA96 (19 mg, 72% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH:13]([CH:16]1[CH:20]2[C:21]3[C:26]([CH:17]1[CH2:18][CH2:19]2)=[CH:25][CH:24]=[CH:23][C:22]=3[NH2:27])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH:13]([CH:16]1[CH:20]2[C:21]3[C:26]([CH:17]1[CH2:18][CH2:19]2)=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])([CH3:15])[CH3:14]
Reactant: CC(C)C1C2CCC1c1c(N)cccc12
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: Cc1ccccc1
Product: CC(C)C1C2CCC1c1c(NC(=O)c3cn(C)nc3C(F)F)cccc12
Temperature: 85 °C
Reaction time: 1 h

Procedure:
15.1 g (0.0752 mol, 96.5% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 100 ml of toluene. The solution was evacuated to 350 mbar and heated to 85° C. Subsequently, within 60 min, 20 g (0.074 mol, 75%; 65:10 syn/anti isomer mixture) of 9-isopropyl-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-ylamine, dissolved in 100 ml of toluene, were metered in and the reaction mixture was stirred for another 1 hour. After venting and cooling to 25° C., the mixture was stirred overnight. Subsequently, the mixture was concentrated under reduced pressure and dried. The yield was 31.3 g; according to 1H NMR 70% pure (82%).