Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[N:26]([C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)ccc3F)OCC[C@H]2CS1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N=[N+]=[N-])ccc3F)OCC[C@H]2CS1
Temperature: 80 °C
Yield: 36.5 %

Procedure:
A suspension of tert-butyl ((4aR,7aR)-7a-(5-bromo-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (300 mg, 0.696 mmol), sodium azide (274 mg, 4.21 mmol), trans-1,2-(bismethylamino)cyclohexane (0.073 mL, 0.464 mmol), 0.66 M aqueous L-ascorbic acid sodium salt (0.780 mL, 0.515 mmol) and 0.33 M aqueous copper(II) sulfate pentahydrate (0.936 mL, 0.309 mmol) in ethanol (3.6 mL) and water (0.70 mL) was heated to 80° C. for 1 h. Water was added and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by preparative TLC on silica gel (0.50 mm thickness) eluting with 30% EtOAc/Hexane to give tert-butyl ((4aR,7aR)-7a-(5-azido-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (100 mg, 0.254 mmol, 36.5% yield) as a white foam. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.30-7.24 (m, 1H), 7.09 (dd, J=10.7, 8.7 Hz, 1H), 7.05-6.93 (m, 1H), 4.23-4.02 (m, 2H), 3.29 (d, J=12.7 Hz, 1H), 2.95 (br. s., 2H), 2.45-2.32 (m, 1H), 2.27-2.15 (m, 1H), 1.50 (s, 9H). MS (M−1): 392.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCN(CC)CC.Cl.[Cu]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:6]=[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(Br)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: C#CCCCCCCCCCCCC
Agent: [Cu]Br
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC#Cc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Temperature: 90 °C
Yield: 49.1 %

Procedure:
A mixture of ethyl{(4-bromobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate (100 mg, 0.23 mmol), 1-tetradecyne (66 mg, 0.34 mmol), copper(I) bromide (4.5 mg, 0.031 mmol) and palladium tetrakis(triphenylphosphine) (11 mg, 0.0095 mmol) in Et3N (1 mL) was heated at 90° C. for 75 min. After cooling to rt, the reaction mixture was diluted with an aqueous HCl solution (1N, 10 mL) and extracted with Et2O (2×20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduce pressure. The residue was purified by flash chromatography (cyclohex./Et2O 4:1) to give the title compound as yellow oil (63 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (m, 2H), 7.33 (m, 4H), 7.14 (m, 2H), 4.51 (s, 1H), 4.47 (s, 1H), 4.34 (m, 4H), 2.40 (m, 2H), 1.58-1.26 (m, 23H), 0.88 (m, 3H). HPLC (Condition A), Rt: 8.21 min (HPLC purity: 99.3%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([S:29]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]3)O1.C(=O)([O-])[O-].[Cs+].[Cs+].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[N:3][C:2]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([S:29]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]3)=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3S(=O)(=O)c2ccc(C#N)cc2)OC1(C)C
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nn4)ccc32)cc1
Temperature: 80 °C
Yield: 47.2 %

Procedure:
394 mg 2-lodo-5-methoxypyridine, 144 mg 3-Chloro-6-trifluormethyl-pyridazine, 323 mg 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile, 2.56 g cesium carbonate and 23 mg fluoroboric acid tri-tert-butylphosphine adduct were dissolved in 65 ml tetrahydrofuran. The reaction mixture was degassed with argon and then 88 mg Tris(dibenzylideneacetone)palladium(0) chloroform adduct were added and the mixture heated to 80° C. for two hours. The cooled reaction mixture was diluted with 100 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 160 mg 4-[5-(6-Trifluoromethyl-pyridazin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:29])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:21])[CH2:24][CH2:25]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Product: CC(=O)N1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
1-(1-Acetyl-piperidin-4-yl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-urea was prepared starting from intermediate N and acetyl chloride. MS calcd. for C24H26ClN4O3 [(M+H)+] 453.2, obsd. 453.1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH:31]C(C2C=CC(C3CCOCC3)=C(OCC3CC3)N=2)=O)[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:31][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59 b) as starting materials, MS (EI): m/e=435.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1SC)#[N:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[N:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1c(SC)c(C#N)c(=O)n2ccccc12
Solvent: CC#N
Product: CCOC(=O)c1c(N2CCCCC2)c(C#N)c(=O)n2ccccc12

Procedure:
A mixture of 1.44 g of 3-cyano-1-ethoxycarbonyl- 2-methylthio-4H-quinolizin-4-one and 5.0 ml of piperidine in 10 ml of acetonitrile was heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on a silica gel column using a mixed solvent of ethyl acetate and n-hexane (2:1) as an eluent to obtain 0.95 g of 3-cyano-1-ethoxycarbonyl-2-piperidino-4H-quinolizin-4-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:8]3/[C:9](=[O:11])[NH:10][C:5]4[C:6]/3=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=C1Cc2nc(Cl)ccc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Product: O=C1Nc2ccc(Cl)nc2/C1=C\c1ccc2cn[nH]c2c1
Yield: 67.4 %

Procedure:
The title compound (40 mg, 67%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 30 min) using 5-chloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (33.7 mg, 0.2 mmol) and 1H-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 10.90 (s, 1H), 8.93 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H); MS ESI 297.0 [M+H]+, calcd for [C15H9ClN4O+H]+ 297.1.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.C([O:25]CC)C>C(O)(C)(C)C>[CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][C:7]3=[O:25]
Reactant: CCOCC
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,2β-methylenandrost-4-ene-3,17-dione (0.2 g) in tert-butanol (5 ml) potassium tert-butoxide (0.26 g) is added and the mixture stirred vigorously for 24 hours at room temperature. Then ice water and diethyl ether are added, the ethereal extract washed with water, dried, and concentrated under reduced pressure. The residue is chromatographed on silica gel using n-hexane/ethyl acetate to give 0.15 g of 1,2β-methylenandrost-4-ene-3,6,17-trione. Found: C 81.01, H 8.05. C20H24O2 requires: C 81.04, H 8.16.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([OH:23])=O)[CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[NH2:24][CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:24][CH2:25][C:26]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:27]=4[CH:28]=[CH:29][CH:30]=[N:31]5)=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: NCc1cccc2ncccc12
Product: Cc1ccc(C(=O)NCc2cccc3ncccc23)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N4′-Cyclopropylmethyl-6-methyl-N3-(quinolin-5-ylmethyl)-1,1′-biphenyl-3,4′-dicarboxamide was synthesised from {4′-[(cyclopropylmethylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}carboxylic acid and 5-aminomethylquinoline using method A. NMR: δH [2H6]-DMSO 9.11, (1H, t), 8.91, (1H, dd), 8.65–8.60, (2H, m), 7.95–7.91, (3H, m), 7.84, (1H, dd), 7.78, (1H, d), 7.72, (1H, t), 7.58–7.55, (2H, m), 7.46, (2H, d), 7.41, (1H, d), 4.95, (2H, d), 3.15, (2H, t), 2.27, (3H, s), 1.03, (1H, m), 0.42, (2H, m), 0.23, (2H, m). LCMS: retention time 3.15 min, MH+450.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)c1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(3-trifluoromethylphenyl)-pyrimidine (example A.42) (0.65 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.2 mmol) according to the general procedure IVb. Obtained as a white solid (0.43 g, 48%). MS (EI) 448.0 [(M)+]; mp 102.5° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O>[C:16]1(=[O:26])[N:20]([CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:4]2)[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Yield: 84.8 %

Procedure:
A mixture of 31.8 g of 2-chloromethyl-4-benzylmorpholine and 30.5 g of potassium phthalimide in 200 ml of dimethylformamide is refluxed for 4 hours and then poured into water. The precipitated crystals are collected by filtration and dried to give 40.2 g of 2-phthalimidomethyl-4-benzylmorpholine. To 400 ml of the ethanol solution of this product is added dropwise a solution of 12.3 g of hydrazine hydrate in 100 ml of ethanol. Further, the resultant mixture is refluxed for 30 minutes. After cooling, insoluble materials are filtered off and the filtrate is concentrated under reduced pressure to give 2-aminomethyl-4-benzylmorpholine as an oily substance. To the solution of 10.3 g of the obtained product in 400 ml of ethanol and 40 ml of water are added 11 g of concentrated hydrochloric acid and 1.1 g of 10% palladium-carbon and the mixture subjected to catalytic reduction at ordinary temperature and atmospheric pressure. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol-acetone to give 2-(aminomethyl)morpholine dihydrochloride as white crystals, melting at 215°-218° C.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[CH:11][C:12]([NH2:17])=[C:13]([CH:16]=1)[CH2:14][NH2:15]>CCOC(C)=O>[NH:17]1[C:12]2[C:13](=[CH:16][CH:9]=[CH:10][CH:11]=2)[CH:14]=[N:15][CH2:1]1
Reactant: NCc1cc(Br)ccc1N
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C1=NCNc2ccccc21
Temperature: 25 °C

Procedure:
To toluene (200 mL), 5-bromo-2-amino-benzylamine (9.5 g, 47.2 mmol) and trimethylbenzoic orthoester (8.2 g, 47.2 mmol) were added, followed by p-toulensulfonic acid (1.35 g, 7.1 mmol). The resulting suspension was stirred at reflux for 50 hours. The reaction mixture was cooled at r.t., diluted with AcOEt (150 mL), washed with saturated sodium bicarbonate, then with water. The organic layer was dried and concentrated to provide the intermediate dihydroquinazoline as a light brown solid (8.5 g; 63%). This intermediate is dissolved in DCM (20 mL) at r.t., then MnO2 (5.1 g) was added. The resulting mixture was stirred at r.t. for 48 hrs, then filtered on celite. The filtrate was concentrated to provide the title product as white solid (8.1 g, 95%). C14H9BrN2; MW: 285.15; MS m/z: 286 (M+1). 1H-NMR (300 MHz, d6-DMSO) ppm: 7.58-7.61 (m, 3H), 8.02 (d, 1H), 8.17 (dd, 1H), 8.49-8.56 (m, 3H), 9.70 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([CH2:15][CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[C:15](\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccccc1F
Yield: 126 %

Procedure:
2-Fluorobenzaldehyde (5.0 g, 40.3 mmol) was dissolved in 150 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (42 g; 116 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes, and the solid was filtered. The filtrate was evaporated in vacuo, then dissolved in ether and filtered through a plug of silica gel using ether as eluent. The solvents were evaporated in vacuo to afford the title compound (10.57 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.70 (s, 1H), 7.26-7.38 (m, 3H), 7.17 (m, 2H), 4.28 (q, J=7.12 Hz, 2H), 2.04 (s, 3H), 1.35 (t, J=7.12 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[N:10])[CH2:5][CH2:4]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O.Cl>N1C=CC=CC=1>[S:11]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[N:10])[CH2:5][CH2:4]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: N#CC1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.20 g of the 4-(hydroxymethyl)cyclohexanecarbonitrile obtained in 5 ml of pyridine was treated portionwise with 2.46 g of tosyl chloride at room temperature and while gassing with argon. After stirring at room temperature for 3.5 hours (formation of a white precipitate), the mixture, cooled to 0° C., was treated with about 2 ml of water, cautiously made acid with about 7 ml of concentrated hydrochloric acid and extracted three times with 30 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated, there remaining behind 2.31 g of a semi-crystalline oil. Low-pressure chromatography (0.5 bar) on 480 g of silica gel using 30% ethyl acetate/petroleum ether as the eluant gave 1.06 g (42%) of trans-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, crystallizing oil (m.p. 84°-85° C.) and 1.03 g (41%) of cis-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, viscous oil. Rf values (30% ethyl acetate/petroleum ether): trans product 0.25, cis product 0.20.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:19]1([C:2]2[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: COc1cc(-c2ccc(F)cc2)c(Br)cc1C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(F)cc2)c(C2CC2)cc1C=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
2-Bromo-4′-fluoro-5-methoxybiphenyl-4-carbaldehyde (20.6 g), cyclopropylboronic acid (10.3 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (4.10 g), tris(dibenzylideneacetone)dipalladium(0) (4.27 g), and a 2 M aqueous sodium carbonate solution (100 mL) were added to toluene (250 mL) in an argon atmosphere, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and poured to water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column (hexane/ethyl acetate), and then, the filtrate was concentrated. The residue was crystallized from a mixed solution of ethanol (50 mL) and water (10 mL), and the obtained crystals were washed with ethanol (85 mL) to obtain the title compound (9.70 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][NH:7][C:6]=2[CH:20]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:31]([C:28]3[CH:29]=[CH:30][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[C:6]=2[CH:20]=1
Reactant: FC(F)(F)c1ccc2c(n1)Nc1ccc(Br)cc1NC2
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1

Procedure:
A solution of 8-bromo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (5.16 g, 15 mmol, intermediate 36), (4-tert-butylphenyl)sulfonyl chloride (10.5 g, 45 mmol), pyridine (7.11 g, 90 mmol), DMAP (0.366 g, 3 mmol in DCM (75 mL) was stirred at rt for 24 h. The reaction was quenched with water, and the product was extracted with EtOAc (3×). The combined extracts were washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from DCM and hexanes to afford the title compound. LC/MS: m/e 542.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.76 (1H, d, J=2.3 Hz), 7.56 (1H, d, J=7.3 Hz), 7.36 (1H, dd, J=8.7, 2.3 Hz), 7.11 (2H, d, J=8.5 Hz), 7.09 (1H, d, J=7.5 Hz), 6.96 (2H, d, J=8.4 Hz), 6.72 (1H, s), 6.62 (1H, d, J=8.7 Hz), 4.70-4.90 (2H, br), 1.25 (9H, s).
Reaction SMILES: [CH3:1][CH:2]1[C:13]2[C:14]3[C:6](=[CH:7][N:8]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:9]=3[CH:10]=[CH:11][C:12]=2[O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(Cl)Cl.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[F:21][C:19]([F:20])([F:22])[S:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH:7]=[C:6]3[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[C:13]=1[C:14]=23)(=[O:17])=[O:18]
Reactant: CC1c2c(OS(=O)(=O)C(F)(F)F)ccc3c2c(cn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1NCCc2cn(S(=O)(=O)c3ccccc3)c3ccc(OS(=O)(=O)C(F)(F)F)c1c23
Reaction time: 1 h

Procedure:
tert-Butyl 6-methyl-1-(phenylsulfonyl)-7-{[(trifluoromethyl)sulfonyl]oxy}-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 16 (12.6 mg, 0.022 mmol) was dissolved in a 50/50 mixture of DCM/TFA (1 mL) and left at room temperature for one hour. The evaporated crude product was purified by preparative HPLC (ACE C8 5 mm, water containing 0.1% TFA —CH3CN) to give 7.2 mg of the title compound as a light brown oil. MS m/z 474 [M+H]+.