Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2I.[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][O:25][C:26]2[CH:31]=[C:30]([Sn](C)(C)C)[N:29]=[C:28]([S:36]([CH3:39])(=[O:38])=[O:37])[N:27]=2)=[CH:22][CH:21]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:30]1[CH:31]=[C:26]([O:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:41][CH:40]=2)[N:27]=[C:28]([S:36]([CH3:39])(=[O:38])=[O:37])[N:29]=1
Reactant: COc1ccc(COc2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)cc1
Reactant: Brc1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 90 °C
Yield: 44 %

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.82 g, 2.015 mmol) and 4-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidine (1.013 g, 2.216 mmol) in DMF (5 mL) followed by Pd(PPh3)4 (0.116 g, 0.101 mmol) and CuI (0.017 ml, 0.504 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 90° C. for 30 min. The mixture was diluted with DCM (5 mL), filtered through a plug of celite and washed with DCM. The filtrate was washed with water (25 mL×3) and the organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-10% EtOAc in Hexanes) to give 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (508 mg, 0.886 mmol, 44.0% yield) as a white foam. MS (ESI, pos. ion) m/z: 573/575 (1:1) (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 1.67-1.86 (m, 3 H) 2.06-2.26 (m, 2 H) 2.49-2.64 (m, 1 H) 3.48 (s, 3 H) 3.72-3.80 (m, 1 H) 3.82 (s, 3 H) 3.91-4.01 (m, 1H) 5.52 (s, 2 H) 5.79 (dd, J=8.41, 2.93 Hz, 1 H) 6.93 (m, J=8.80 Hz, 2 H) 7.45 (m, J=8.80 Hz, 2 H) 7.51-7.60 (m, 2 H) 7.70 (s, 1 H) 8.68-8.74 (m, 1 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[O:10]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:5]=2)[NH:1]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=S(=O)(O)Cl
Product: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
1,3-Dihydro-indol-2-one 13 (4.43 g, 33.3 mmol) was added slowly to cold chlorosulfonic acid (9 ml, 135 mmol). The reaction temperature was maintained below 30° C. during the addition. After the addition, the reaction mixture was stirred for 2 h at room temperature, then heated to 68° C. for 1 h, cooled and poured into ice water. The precipitate was washed with water and dried under vacuum to give 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 14 (5.4 g, 70%). MS m/z 229 [MH]+. 1H NMR, CD3CN 8.91 (S, 1H), 7.90-7.95 (m, 2H), 7.04 (d, J=0.11, 1H), 3.57 (S,1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([OH:18])=O)=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:50][C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:16]([NH:56][CH2:55][C:54]2[CH:57]=[CH:58][C:51]([F:50])=[CH:52][CH:53]=2)=[O:18])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Br)ccc1OCc1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 3-(benzyloxy)-6-bromopicolinic acid (1.90 g, 6.2 mmol), HATU (4.69 g, 12.4 mmol) and Et3N (0.5 mL) in DMF (20 mL) was added 4-fluorobenzylamine (2.30 g, 18.5 mmol) dropwise. The mixture was stirred at room temperature overnight. Then it was concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash gel chromatography (PE:EtOAc=2:1) to afford the product of 3-(benzyloxy)-6-bromo-N-(4-fluorobenzyl)picolinamide (2 g, yield: 77.8%). 1H-NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 7.42˜7.45 (m, 3H), 7.23˜7.37 (m, 6H), 6.97 (t, J=8.8 Hz, 2H), 5.21 (s, 2H), 4.57 (d, J=6.0 Hz, 2H). MS (M+H)+: 415/417.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]([CH3:19])[C:8]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]([CH3:19])[C:8]([C:10]1[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: CSc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Yield: 69 %

Procedure:
To a suspension of 3.50 g (7.17 mmol) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 0.213 g (0.2 mmol) tetrakis-(triphenylphosphin)palladium and 0.96 g (7.89 mmol) phenylboronic acid in 40 ml 1,2-dimethoxyethane a solution of 0.83 g (7.89 mmol) Na2CO3 in 15 ml H2O was added. The resulting reaction mixture was heated at reflux for 16 hrs. After evaporation of the 1,2-dimethoxyethan, the aqueous phase was extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) and crystallised to give 2.4 g (69%) 2-methylsulfanyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as off-white crystalls, m.p 109.7-110.7°.
Reaction SMILES: [Zn](CC)CC.[CH3:6][O:7][C:8](=[O:29])[N:9]([C@H:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH3:21])[CH2:10][CH2:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].ClCCl>ClCCCl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][C:12]([OH:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH2:10][N:9]([C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH3:21])[C:8]([O:7][CH3:6])=[O:29]
Reactant: COC(=O)N(CCC(=O)c1ccccc1)[C@@H](C)c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CC(O)(CCN(C(=O)OC)[C@@H](C)c1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Et2Zn (1 M in hexane, 55 mL) was added dropwise to [(S)-1-(4-chloro-phenyl)-ethyl]-(3-oxo-3-phenyl-propyl)-carbamic acid methyl ester (3.80 g) dissolved in 1,2-dichloroethane (30 mL) and chilled to 0° C. under argon atmosphere. Then, (Ph3P)3RhCl (0.50 g) was added followed by the dropwise addition of methyl bromoacetate (1.0 mL) dissolved in 1,2-dichloroethane (10 mL). The resulting solution was stirred at 0-5° C. for 1 h and at ambient temperature for another 1.5 h. The solution was poured into ice-cold half-saturated aqueous NH4Cl solution (150 mL). After addition of dichloromethane, the mixture was filtered through Celite that was extracted with an additional portion of dichloromethane. The organic phase was separated and washed with water and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 85:15→70:30) to give the title compound as a mixture of two diastereomers.
Reaction SMILES: [C:1]1([S:7]([C:10]2[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[C:1]1([S:7]([C:10]2[S:14][C:13]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)c2ccccc2)s1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(S(=O)(=O)c2ccccc2)s1
Yield: 40 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-benzenesulfonyl-thiophene-2-sulfonyl chloride (17.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 40% yield (8.9 mg). MS (ESI+) calcd mass for C17H13N5O4S3 447.012966, found 447.013676.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:18][C:19](=[O:22])[CH2:20]Cl)[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.[N-:25]=[N+:26]=[N-:27].[Na+]>CC(C)=O>[N:25]([CH2:20][C:19]([NH:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23])=[O:22])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)C(=O)N1
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 95 %

Procedure:
To a suspension of N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-chloroacetamide (1.53 g, 4.4 mmol) in acetone (30 ml) was added sodium azide (0.43 g, 6.6 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo to give 1.49 g (96%) of product as an off-white solid: 1H NMR (DMSO-d6) δ 11.19 (s, 1H), 10.20 (s, 1H), 8.49 (d, J=8.3 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.1 and 12.7 Hz, 1H), 4.34 (s, 2H), 2.99-2.84 (m, 1H), 2.65-2.47 (m, 2H), 2.09-2.00 (m, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH:25]([C:27]1[N:28]=[C:29]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[S:30][CH:31]=1)=O.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[Br:21][C:20]([Br:24])=[CH:25][C:27]1[N:28]=[C:29]([CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]2)[S:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C=C(Br)Br)cs2)CC1
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To a solution of triphenylphosphine (7.08 g, 27 mmol) in anhydrous dichloromethane (11 ml) was added dropwise a solution of carbon tetrabromide (4.3 g, 13 mmol) in anhydrous dichloromethane (5 ml) at 10° C., and the mixture was stirred at the same temperature for 15 mins. Stirring was stopped, the supernatant of the reaction mixture was collected, and a solution of tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.0 g, 3.4 mmol) in anhydrous dichloromethane (11 ml) was added dropwise at 10° C. After stirring at 5-10° C. for 40 mins, triethylamine (4 ml) and saturated aqueous sodium hydrogen carbonate solution (0.5 ml) were added. The mixture was filtered through a Celite pad, and the insoluble material was washed with dichloromethane. The filtrate and washing solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to give tert-butyl 4-[4-(2,2-dibromovinyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.5 g, yield 97%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:27]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])=[O:29])[NH:10][C@H:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[C@:12]2([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: OC[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)N2CCC[C@H]2CO)[C@@H](c2cccc(Cl)c2)[C@]1(C#N)c1ccc(Cl)cc1
Yield: 11.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with (S)-1-pyrrolidin-2-yl-methanol (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3S,4S,5S)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-pyrrolidine-3-carbonitrile (12.0 mg, 11.7%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1
Reactant: N
Solvent: ClC(Cl)Cl
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of yellow mercuric oxide (0.74 g, 0.036 mol), N-[3-(2,4,6-trifluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.27 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirred for 1 day at room temperature. The solvent was removed-in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent, trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.63 g (52%), m.p. 161°-162 ° C.
Reaction SMILES: [NH2:1][N+:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH:29]=O.[OH-].[K+]>O1CCOCC1.O>[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[C:29]1[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][N:2]2[N:1]=1
Reactant: Cc1cccc(C)c1C=O
Reactant: COC(=O)c1ccc(N)[n+](N)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c(C)cccc3C)nn2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a solution of methyl 1,6-diaminopyridin-1-ium-3-carboxylate; 2,4,6-trimethylbenzenesulfonate (6.0 g, 16.3 mmol) in 1,4-dioxane (50 mL) is added 2,6-dimethylbenzaldehyde (1.72 g, 13.00 mmol) and the reaction mixture is heated at 90° C. for 2 hours. The reaction mixture is cooled to room temperature, 1 N KOH solution (15 mL) is added, and the mixture is stirred overnight at room temperature. The reaction mixture is diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts are washed with water (100 mL) and saturated brine solution (100 mL), dried over sodium sulphate, filtered, and concentrated. The crude material is purified by silica gel chromatography (combiflash) eluting with 12% EtOAc in hexanes to give the title compound as a yellow liquid (0.35 g, 16%). LCMS m/z 282 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:19]>>[O:11]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:8](=[O:19])[CH2:9][CH:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: CO
Agent: Cl
Product: O=C1CC(c2ccccc2)Oc2ccccc21
Reaction time: 30 h

Procedure:
General procedure C for deprotection of the MOM group from chalcones to synthesize 7b, 7d, 7f. Concd HCl (0.25 mL/MOM group) was added to a solution of chalcone (1 mmol) in methanol (10 mL) at room temperature and the reaction mixture was stirred for 24-36 h until disappearance of starting material. The solvent was evaporated under reduced pressure and the residue was column chromatographed eluting with 25% ethyl acetate in hexanes to afford flavanone in high yield.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.[C:26](Cl)(=O)[CH3:27]>CN(C)C=O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:11][N:12]([CH2:13][CH2:26][CH3:27])[CH2:6][CH2:5][CH3:4])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccn1)=NC2
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-trifluoromethyl-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetrapropyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N',N'-tetrapropyldiaminomethane) are reacted together to give 8-trifluoromethyl-1-[2-(dipropylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4-]benzodiazepine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:20][CH2:19]1>>[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([NH:26][C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=4[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: Nc1cccc(CSC2CC2)c1
Product: COc1cc(F)ccc1-c1nc(Nc2cccc(CSC3CC3)c2)ncc1F

Procedure:
Intermediate 48.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(cyclopropylsulfanyl)-methyl]aniline. The batch was purified by chromatography (hexane/ethyl acetate 30%) to give the desired product.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>[OH-].[Na+].C(O)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])=[CH:14][CH:13]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: Cc1ccc(CBr)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CSC[C@H](N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
L-Cysteine hydrochloride monohydrate (2.0 g) is dissolved in a 2 N aqueous sodium hydroxide solution (11.4 ml). To the solution is added a solution of α-bromo-p-xylene (2.3 g) in ethanol (10 ml). The mixture is stirred at room temperature for 40 minutes, and precipitating crystals are filtered off. The obtained crystals are purified by recrystallization to give the titled compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[OH:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[OH:26][CH:27]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[C:28]([NH:16][CH2:15][CH2:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=1)=[O:29]
Reactant: C#CCOc1ccc(CCN)cc1OC
Reactant: Cc1ccc(CC(O)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CCNC(=O)C(O)Cc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (11.5 g, 47 mmol) and N,N-diisopropylethylamine (23 g, 0.18 mol) are dissolved in 100 ml of N,N-dimethylformamide. To this solution 2-hydroxy-3-p-tolyl-propionic acid (8.1 g, 45 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (22 g, 49 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 1:1) to afford 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-3-p-tolyl-propionamide (E1.16).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[N:24]1([CH2:23][CH2:22][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: ClCCN1CCOCC1
Reactant: NC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCCN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Potassium carbonate (15.1 g, 109 mmol, 3 eq.), acetonitrile (73 mL) and then 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq.) are placed in a 250 mL round-bottomed flask. The suspension is stirred for 30 minutes, followed by addition of 4-(2-chloroethyl)morpholine hydrochloride (8.82 g, 47 mmol, 1.3 eq.). 10 mL of dimethylformamide are added to this suspension, and the mixture is then stirred at a temperature in the region of 40° C. for 16 hours. The solvent is then evaporated off and the residue is diluted with water and extracted with dichloromethane. The aqueous phase is acidified with 5 N hydrochloric acid and reextracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. 4-(2-Morpholin-4-ylethoxy)benzamide 2.17 g (23%) is thus obtained in the form of a white solid, which is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7](Br)[CH:8]=[CH2:9].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:9]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH:8]=[CH2:7]
Reactant: C=CCBr
Reactant: Cc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1cnc(C)c1
Yield: 38 %

Procedure:
4-Methylimidazole (2.0 g, 24.36 mmol), allyl bromide (2.2 mL, 24.36 mmol), N,N-diisopropylethylamine (5.0 mL, 29.24 mmol) in DMF (50 mL) were stirred at 80° C. overnight. Then the reaction mixture was cooled, quenched with saturated NaHCO3 (30 mL), and extracted with CH2Cl2 (4×40 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a brown oil. Purification by flash column chromatography on silica using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (1.13 g, 40%). 1H NMR (CDCl3) (as a mixture of regio-isomers) δ 2.17 and 2.22 (s, total 3H), 4.44-4.48 (m, total 2H), 5.19-5.24 (m, total 2H), 5.89-6.00 (m, total 1H), 6.61 and 6.79 (s, total 1H), 7.35 and 7.39 (s, total 1H).