Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.N[C@H]1C(=O)NC2C=CC=CC=2O[C@H]1C.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:34][C@@H:35]1[C:41](=[O:42])[NH:40][C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][C@H:36]1[CH3:47])=[O:33])=[CH:26]2.FC(F)(F)C(O)=O.N[C@@H]1C(=O)NC2C=CC=CC=2O[C@H]1C>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:34][C@H:35]1[C:41](=[O:42])[NH:40][C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][C@H:36]1[CH3:47])=[O:33])=[CH:26]2
Reactant: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1N
Agent: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1N
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
The title compound was prepared from (2S,3R)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate salt by the procedures described for the preparation of (2S,3S)-3-(5-chloroindole-2-carbonylamino)-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Example 22) from (2S,3S)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate salt. HPLC/MS [M+H]+, 370.
Reaction SMILES: [C:1](=[O:38])([O:8][CH:9]1[CH2:13][CH:12]([OH:14])[C@H:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[C@H:10]1/[CH:26]=[CH:27]/[C@@H:28]([OH:37])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[I-:39].[Na+]>CC(C)=O>[C:1](=[O:38])([O:2][CH2:3][CH2:4][CH2:5][CH2:6][I:39])[O:8][CH:9]1[CH2:13][CH:12]([OH:14])[C@H:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[C@H:10]1/[CH:26]=[CH:27]/[C@@H:28]([OH:37])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: [I-]
Reactant: CCNC(=O)CCC/C=C\C[C@H]1C(O)CC(OC(=O)OCCCCCl)[C@@H]1/C=C/[C@@H](O)CCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCNC(=O)CCC/C=C\C[C@H]1C(O)CC(OC(=O)OCCCCI)[C@@H]1/C=C/[C@@H](O)CCc1ccccc1
Yield: 79.7 %

Procedure:
4-Chlorobutyl (2R,3R)-3-[(2Z)-7-(ethylamino)-7-oxohept-2-en-1-yl]-4-hydroxy-2-[(1E,3S)-3-hydroxy-5-phenylpent-1-en-1-yl]cyclopentyl carbonate (g-1; 25 mg, 0.045 mmol) was dissolved in acetone (0.9 mL). Sodium iodide (68 mg, 0.45 mmol) was added to the solution. The mix was microwaved at 135° C. for 35 mins and then concentrated under reduced pressure. The residue was dissolved in EA+water. EA phase was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 23 mg (80%) crude iodide g-2, which was used immediately without further purification.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1c(Cl)cccc1Cl
Product: Oc1ccc2ncn(-c3c(Cl)cccc3Cl)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,6-dichlorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=279.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:21][O:22][C:23]([N:25]=[C:26]=S)=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C.C1C=CC=CC=1>[CH3:21][O:22][C:23]([NH:25][C:26]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]([C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:3][C:2]=2[N:1]=1)=[O:24]
Reactant: COC(=O)N=C=S
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: CC#N
Product: COC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)OC)ccc2[nH]1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 2-[(3,4-diaminophenyl)carbonyl]benzoate (134 mg, 0.50 mmol) in a mixture of acetonitrile-benzene (1:1, 5 mL) methyl isothiocyanatidocarbonate (70 mg, 0.60 mmol) was added followed by the addition of DCC (153 mg, 0.75 mmol) and the reaction mixture was heated to reflux for 18 h. After cooling to room temperature the reaction mixture was concentrated. The residue was triturated with diethyl ether (2×, 10 mL) and the pale orange solid was collected by filtration to give methyl 2-[(2-{[(methoxy)carbonyl]amino}-1H-benzimidazol-5-yl)carbonyl]benzoate (125 mg, 71%). MS (EI) for C18H15N3O5: 354 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[N:15]1([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:18]1[CH2:19][CH2:20][N:15]([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:16][CH2:17]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Product: Cc1c(C(O)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-(1-Hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzo furan-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one and 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[N:26]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[CH:62])=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C>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.CN(C=O)C>[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:30]3[CH:31]=[CH:32][C:27]([C:25]4[N:26]=[C:22]([CH:12]5[CH2:13][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:15][CH2:16][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:34])[CH:6]([CH3:8])[CH3:7])[NH:23][CH:24]=4)=[CH:28][CH:29]=3)=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41]
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
{1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (71.2 mg, 0.181 mmol) and Pd(PPh3)4 (21.5 mg, 0.018 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (181 mg, 1.8 mmol) and copper(I) iodide (3.5 mg, 0.018 mmol). The mixture was heated at 80° C. After 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2,2,2-trifluoro-ethyl)-piperazin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (12.4 mg): LCMS-ESI+: calc'd for C44H52F3N9O6: 859.9 (M+); Found: 860.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.91-7.68 (m, 10H), 6.06 (m, 2H), 5.24 (m, 1H), 4.43 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.11 (m, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.49-3.45 (m, 2H), 3.15-3.02 (m, 3H), 2.77 (m, 1H), 2.58 (m, 1H), 2.29-2.01 (m, 5H), 1.07-0.83 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1>>[C:22]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:23]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Product: O=C(O)CCc1ccc(OCc2cccc(Nc3cccc(-c4ccccc4)c3)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 298 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and biphenyl-3-ylamine. colorless crystals (yield 6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.O>[NH2:14][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)Cc1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-butyl{2-[(diphenylmethylidene)amino]-pyridin-4-yl}acetate (35 mg, 0.94 mmol) was dissolved in 1:1 mixture of THF/water (5 mL) and treated with 500 μL of a 1N aqueous hydrochloric acid solution. The reaction was allowed to stir at ambient temperature for 30 minutes and then concentrated in vacuo. The crude residue was dissolved in DCM and washed with a saturated aqueous sodium bicarbonate solution. The organic layers were dried over sodium sulfate, filtered and concentrated to afford crude title compound which was used without further purification: LC-MS: (M+H)+209.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[NH:6][N:7]=1.C(N(CC)CC)C.[CH:25]([CH:27]=[CH2:28])=[O:26]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[N:6]([CH2:28][CH2:27][CH:25]=[O:26])[N:7]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]nc(Br)c1=O
Reactant: C=CC=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=CCCn1nc(Br)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
To a stirring solution of 6-bromo-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.46 g, 4.93 mmol) in dry N,N-Dimethylformamide (DMF) (64.9 ml), TRIETHYLAMINE (0.825 ml, 5.92 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Acrolein (0.366 ml, 4.93 mmol) was then added and the mixture was left stirring at room temperature for 3 hours. It was then quenched with NH4Cl saturated solution and diluted with AcOEt. Phases were separated, organic phase was washed with cold water, dried over sodium sulphate, filtered and concentrated under reduced pressure affording 3-[6-bromo-3,5-dioxo-4-(phenylcarbonyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl]propanal (1.8 g, 5.11 mmol). The compound was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a solution of N-(2-methoxyethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (0.1 g, 0.34 mmol) in anhydrous acetonitrile (10 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (0.097 g, 0.34 mmol) and N,N-diisopropylethylamine (0.059 mL, 0.34 mmol). The resulting mixture was heated to reflux and stirred under nitrogen for 3 h. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 mL) and CH2Cl2 (40 mL), the organic extract was separated by hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 12 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (90 mg).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([N:13]=[C:14]=[S:15])[C:10]([CH3:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)#[N:2].[CH2:17]([NH2:20])[CH2:18][NH2:19]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:12]=[C:11]([NH:13][C:14]([NH:19][CH2:18][CH2:17][NH2:20])=[S:15])[C:10]([CH3:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)#[N:2]
Reactant: Cc1c(N=C=S)cc(C#N)c2cccnc12
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)cc(C#N)c2cccnc12
Reaction time: 0.17 h

Procedure:
A solution of 5-cyano-8-methyl-7-quinolinylisothiocyanate (0.85 g) in toluene (100 mL) is added dropwise to a solution of 1,2-ethylenediamine (1.94 g) in toluene (100 mL). A yellow-white precipitate is observed after the reaction stirs at room temperature for 10 minutes. The precipitate is filtered and dried in vacuo to afford N-(5-cyano-8-methyl-7-quinolinyl)-N'-2-aminoethylthiourea as a yellow-white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH2:22][C:21](=O)[N:11]3[CH2:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH:10]3[CH2:9]2)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>CN(P(N(C)C)(N(C)C)=O)C>[S:45]=[C:21]1[N:11]2[CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:10]2[CH2:9][NH:8][CH2:22]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC2c3ccccc3CCCN12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: S=C1CNCC2c3ccccc3CCCN12
Reaction time: 3 h

Procedure:
A mixture of 2-(triphenylmethyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino-[2,1-a][2]benzazepine (0.66 g) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide) (0.29 g) in HMPA (10 ml) was heated to 80° under a nitrogen atmosphere. The mixture was stirred at this temperature for 3 hr, cooled and partitioned between water and diethyl ether. The organic layer was washed with water and evaporated to a yellow foam. This residue was dissolved in acetone (20 ml), cooled to 0° and concentrated hydrochloric acid (0.5 ml) added. After stirring at room temperature for 30 min the mixture was evaporated and the residue partitioned between dilute hydrochloric acid and chloroform. The aqueous fraction was basified with sodium carbonate and extracted with chloroform. This chloroform fraction was washed with brine, dried (K2CO3) and evaporated to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[NH:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:15]>C(#N)C>[Cl:15][C:4]1[C:5]2[NH:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2nc(C)[nH]c(=O)c2[nH]1
Solvent: CC#N
Product: Cc1nc(Cl)c2[nH]c(C)cc2n1

Procedure:
2,6-Dimethyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one from example A6 (87.00 g; 0.53 mol) is suspended in dry acetonitrile (870 mL). After addition of POCl3 (122 mL; 1.33 mol) the stirred reaction mixture is heated to gentle reflux for 18 hours.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([CH:5]1[CH2:6][CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Reactant: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Product: O=C(NCC1CC(C(=O)Nc2ccc(N3CCOCC3=O)cc2F)CC1O)c1ccc(Cl)s1

Procedure:
In analogy to example 21C, (1SR,3RS,4SR)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1RS,2SR,4SR)-4-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentylmethyl}-amide. Orange solid. MS: 496.3. ([M+H]+).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Si:10]([O:17][CH:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)O)=[C:20]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[C:19]1=2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Si:10]([O:17][CH:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([CH:35]([F:7])[C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][CH:38]=3)=[C:20]([C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[C:19]1=2)([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O[Si](C)(C)C(C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O[Si](C)(C)C(C)(C)C)C1

Procedure:
1.46 g of diethylaminosulphur trifluoride dissolved in 10 ml of toluene were added dropwise at −5° C. to 3.8 g of [5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7, 8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol dissolved in 37.8 ml of toluene. The reaction was quenched after 30 minutes using saturated aqueous sodium hydrogencarbonate solution and the organic phase was washed again using saturated aqueous sodium hydrogencarbonate solution and dried. After distilling off the solvent in vacuo, the residue was recrystallized from ethanol. A total of 3.33 g of colorless crystals having a purity of 99.4% according to HPLC resulted. By chromatography on silica gel, it was possible from the mother liquor of the crystallization, using petroleum ether/ethyl acetate 10:1, to obtain a further 0.26 g of the same quality.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.C([Li])CCC.CC(O)C.C(=O)=O.CN(C)[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[OH:39][C:32]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5]2[C:6](=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7](=[O:8])[N:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)c1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc2c(c1)C(O)(c1ccccc1)N(c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
While cooling in a dry ice/isopropanol bath, to a solution of 1 (3.00 g, 13.2 mmol) in tetrahydrofuran at −78° C. was added dropwise n-butyllithium (2.5M in hexanes, 11.1 mL, 27.8 mmol). After stirring for 0.5 h the reaction mixture was warmed over 0.5 h to −15° C. It was recooled in the IPA/dry ice bath then a tetrahydrofuran solution of N,N-dimethylbenzamide (2.38 g, 15.8 mmol) was added. The reaction mixture was warmed to room temperature and quenched with water. The solvent was removed in vacuo. Sat. sodium bicarbonate was added and the mixture extracted with ethyl acetate (3×). The combined organic portions were dried with sodium sulfate (anh.), filtered, and concentrated. A solid resulted. It was triturated with ether to give 2 as a white solid (3.11 g, 71%)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[BH4-].[Na+]>CCO.CCOC(C)=O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a solution of 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (P-3; 2.59 g, 7.79 mmol) in EtOH (120 mL), sodium borohydride (725.8 mg, 19.18 mmol) was added as a solid in portions at room temperature. After the addition was complete, the mixture was stirred at room temperature for 90 minutes (min). The mixture was then diluted with EtOAc and washed with H2O. The aqueous fraction was extracted with EtOAc. The organic fractions were combined, dried over anhydrous MgSO4, and evaporated at room temperature under vacuum. The crude material was absorbed to silica gel with EtOAc and eluted with 50% EtOAc in hexane. The title product (2.43 g, 93%) was isolated as a white solid: mp 112-114° C.; 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.29-8.12 (m, 2H), 7.91-7.69 (m, 2H), 7.43 (ddd, J=9.0, 5.7, 4.5 Hz, 4H), 4.78 (d, J=6.0 Hz, 2H), 2.07 (t, J=6.0 Hz, 1H); ESIMS m/z 336 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:13][CH:14]([F:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH2:15][CH:14]([F:17])[F:13]
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: NCC(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC(F)CNc1nc2ccncc2nc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (50 mg, 0.250 mmol) in dioxane (250 μL) was treated with 2,2-difluoroethanamine (21.0 μL, 0.275 mmol) and DIPEA (131 μL, 0.750 mmol). The resulting reaction mixture was stirred at 70° C. for 1 h then purified by flash silica gel chromatography using a gradient of 0% to 60% EtOAc in hexanes to give the title compound (52 mg, 85%) as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][O:39][CH3:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][O:39][CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:34])=[O:35]
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COCCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.33) (265 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (320 mg, 56%). MS (ISP) 569.1 [(M+H)+]; mp 186-188° C.