Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)=[CH:12][C:13]#[N:14]>CO>[CH3:6][O:5][C:1]([C:2]1[S:3][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:12][C:13]=1[NH2:14])=[O:4]
Reactant: N#CC=C(Cl)c1cccc(Cl)c1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium pellets were slowly added to methanol solution to form NaOMe in situ, then methyl thioglycolate was added over a period of 20 minutes to the methanol solution. A solution of 3-Chloro-3-(3-chloro-phenyl)-acrylonitrile in methanol was added slowly and was brought to reflux for 1 hour. The reaction mixture was cooled to room temperature and methanol was concentrated to 100 mL and 200 mL of water was added, stirred for 30 minutes and the yellow precipitate was collected and washed with water several times to yield a yellow crystalline compound, mp 92-95° C. 1H NMR (DMSO-d6) δ1.60 (s, 6H), 7.30 (d, 1H, J=8.41 Hz), 7.41(d, 1H, J=8.41 Hz), 10.47 (s, 1H); MS(+APCI)m/z 213(M+H); Anal. Calc. For C9H9CIN2O2: C, 50.84; H, 4.27; N, 13.17. Found: C, 50.99; H, 4.28; N, 12.98.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[CH2:43][CH2:44]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[CH2:43][CH2:44][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCc1cc(F)c(F)cc1OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(CCI)c(OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of Ph3P (691 mg, 2.63 mmol) and imidazole (179 mg, 2.63 mmol) in DCM (15 mL) was cooled to 0° C. Added to this was iodine (668 mg, 2.63 mmol) and the resulting mixture was stirred at 0° C. for 30 min. 2-(2-(Benzyloxy)-4,5-difluorophenyl)ethanol (580 mg, 2.195 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temperature. After 5 h, the mixture was filtered and washed the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-20% EtOAc/hexane) to give 1-(benzyloxy)-4,5-difluoro-2-(2-iodoethyl)benzene (630 mg, 1.684 mmol, 77% yield) as colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.50-7.34 (m, 6H), 7.00 (dd, J=10.3, 9.2 Hz, 1H), 6.77 (dd, J=12.0, 6.6 Hz, 1H), 5.06 (s, 2H), 3.37 (t, J=7.5 Hz, 2H), 3.21-3.15 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].O1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O.[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18]CC>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>[CH3:8][CH:9]1[C:18]2[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][O:10]1
Reactant: CCCCCCC
Reactant: C1COCCO1
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: [Cs+]
Solvent: O
Product: CC1OCc2ccccc21
Temperature: 135 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
The mixture of sodium 1-(2-bromo-phenyl)-ethoxymethyl trifluoroborate (30 mg, 0.092 mmol) synthesized in Example 20, tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.018 mmol), cesium carbonate (90 mg, 0.28 mmol), 1,4-dioxane (1.0 ml), and water (0.10 ml) was stirred at 135° C. for 90 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, and then water and heptane were added thereto, followed by filtration with Celite. The organic layer of the filtrate was separated and washed with saturated saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with silica gel column chromatography (hexane alone→hexane:diethyl ether=30:1), thereby obtaining the entitled compound (35.7 mg, 41%).
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].[CH3:21]C1C=C(C=CC=1[N+]([O-])=O)C(O)=O>>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[CH:2][C:17]=1[CH3:21]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1N

Procedure:
The following intermediate was prepared in a manner analogous to Intermediate 62 utilising 3-Methyl-4-nitrobenzoic acid, available form Aldrich, as the starting Nitro acid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH2:30])=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:30][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:21]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCc1c[nH]c2ccccc12
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3c[nH]c4ccccc34)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1H-indol-3-ylmethyl amine as described in Step 5, Example 24 to give the title compound. MS: m/e 428 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1)[CH3:19].CN(C1C=CC(CC(O)=O)=CC=1)C.C(Cl)(=O)C(Cl)=O>>[O:11]=[C:9]1[NH:8][C:7](=[O:12])[CH:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([OH:16])=[C:2]([NH:1][C:27](=[O:28])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([N:18]([CH3:19])[CH3:17])=[CH:21][CH:22]=3)[CH:3]=2)[S:10]1
Reactant: Nc1cc(CC2SC(=O)NC2=O)ccc1O
Reactant: CN(C)c1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccc(CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)c1ccc(CC(=O)Nc2cc(CC3SC(=O)NC3=O)ccc2O)cc1

Procedure:
5-(3-amino-4-hydroxybenzyl)-2,4-dioxothiazolidine and 4-(N,N-dimethylamino)phenylacetyl chloride, prepared from 4-(N,N-dimethylamino)phenylacetic acid and oxalyl chloride, are treated in the same manner as described in Example 5-(1) to give N-[5-(2,4-dioxothiazolidin-5-yl)methyl-2-hydroxyphenyl]-2-(4-dimethylaminophenyl)acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[CH2:39][C:40]#[N:41].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CCOC(C)=O.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[C:40]([CH2:39][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])=[CH:29][C:24]=1[F:23])#[N:41]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Reactant: CC1(C)OB(c2ccc(CC#N)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)c(F)c3)c2OC)nc1
Temperature: 110 °C
Yield: 47.2 %

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (50 mg, 0.135 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (70.7 mg, 0.271 mmol), dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II) (8.83 mg, 0.014 mmol) and sodium bicarbonate (56.9 mg, 0.677 mmol) in dioxane (0.60 mL) and water (0.150 mL) was heated at 110° C. in the microwave for 40 min. Additional dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II) was added (10 mg) and the reaction heated at 110° C. in the microwave for 1 h. The reaction mixture was diluted with EtOAc, concentrated onto Celite®, and purified on a 10 g NH silica gel column eluted with 0 to 100% EtOAc in hexanes to 6-(4-(4-(cyanomethyl)-3-fluorophenyl)-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (27 mg, 47.1% yield). MS m/z 424 [M+H]+.
Reaction SMILES: [CH:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.Cl>C1COCC1>[CH:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:14][NH2:15])=[CH:16][CH:17]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(S(=O)(=O)C2CCCCC2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccc(S(=O)(=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Dissolve 4-cyclohexanesulfonyl-benzonitrile (1.27 g, 5.1 mmol) in anhydrous THF (15 mL) at 0° C. under nitrogen and then add a solution of borane-THF complex (15.3 mL, 15.3 mL, 1M solution in THF). Stir overnight while warming to room temperature. Add the reaction to a mixture of 5N aqueous HCl (50 mL), THF (50 mL) and ice and stir for 1 hour. Concentrate the mixture in vacuo and take up the resulting white residue through a SCX-2 column eluting with methanol followed by 3N ammonia in methanol to obtain the title compound as a white solid (625 mg, 50%). MS (ES+) m/z: 254.1 (M+H)+
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:29]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2c[nH]c3ccccc23)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
Acryloyl chloride (0.100 mL, 1M in THF, 0.1 mmol) was added dropwise to a fine slurry of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile (Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 mL, 0.16 mmol) in THF (2 mL) at −10° C. over a period of 2 minutes under N2. The mixture was then stirred at 0° C. for 10 minutes then allowed to warm to r.t. over 20 minutes. The mixture was then cooled again to −10° C. and further acryloyl chloride (0.06 mL, 1M in THF, 0.06 mmol) was added dropwise. The mixture was stirred at 0° C. for a further 10 minutes, then allowed to warm to r.t. over 20 minutes. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH2Cl2 (2 mL). This solution was washed with sat. NaHCO3 (1 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7N methanolic ammonia in CH2Cl2 gave a residue that was washed with CH3OH (0.1 mL) and dried in air to give the title compound (11 mg, 20%) as a cream crystalline solid; 1H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93 (4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H, dd), 6.91 (2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67 (1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES+ MH+ 509.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=[CH:16]3.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][NH:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][N:27]1[C:22]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][C:12]3[CH2:11][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:25][C:13]=3[CH:14]=2)[N:19]=1)=[O:24]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21)N1Cc2ccccc2C1

Procedure:
A mixture of (±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (10 mg, 0.030 mmol, described in Intermediate 19), isoindoline (7 mg, 0.060 mmol), EDC (9 mg, 0.045 mmol), HOBT (7 mg, 0.045 mmol), and N,N-diisopropylethylamine (0.026 mL, 0.151 mmol) was stirred in DMF (1 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3 CN:CF3 CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=433 (M+1). HRMS: m/z=433.1667; calculated m/z=433.1659 for C27H21N4O2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([Cu])#[N:10]>CN(C=O)C>[Br:8][C:4]1[N:3]=[C:2]([C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Br)n1
Temperature: 100 °C
Yield: 28 %

Procedure:
Take up 2,6-dibromopyridine (0.500 g, 2.11 mmol) and CuCN (0.189 g, 2.11 mmol) in DMF (5.3 mL). Heat at 100° C. for 22 hours. Cool to room temperature. Add water (50 mL) and extract with ethyl acetate (3×100 mL). Wash the organic layer with brine (1×75 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 15-40% ethyl acetate in hexanes to give the title compound (0.108 g, 30.0%): GC/MS, MS ES+ 182 (M−H)+, time 8.78 min, % of total 100%; TLC [silica gel 60 F254, 30% ethyl acetate in hexanes] Rf=0.29.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[N:10]=1)=O)C.[NH3:14]>>[C:11]([C:9]1[N:10]=[C:6]([C:4]([NH2:14])=[O:3])[S:7][CH:8]=1)(=[O:13])[CH3:12]
Reactant: CCOC(=O)c1nc(C(C)=O)cs1
Reactant: N
Product: CC(=O)c1csc(C(N)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-acetyl-2-thiazolecarboxylic acid ethyl ester (2.5 g) in 28% aqueous ammonia solution (40 ml) was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration to afford 4-acetyl-2-thiazolecarboxamide (1.76 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH:21]3[C:29]4[C:24](=[C:25]([O:30]COC)[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.Cl>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH:21]3[C:29]4[C:24](=[C:25]([OH:30])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCOc1cccc2c1CCC2N(C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C1CCc2c(O)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
220 mg of 1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-(methoxymethoxy)indane was dissolved in 2 ml of a 25% hydrogen chloride-ethyl acetate solution, followed by stirring at room temperature for 3 hours. After adding water, the reaction solution was neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 167 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:14]=[N:13][CH:12]([NH:15][CH3:16])[NH:11][C:10]1=[O:17].[CH3:18][S:19]([OH:22])(=[O:21])=[O:20]>O>[CH3:18][S:19]([OH:22])(=[O:21])=[O:20].[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH:14]=[N:13][C:12]([NH:15][CH3:16])=[N:11][C:10]1=[O:17]
Reactant: CNC1N=CN(c2c(C)cccc2C)C(=O)N1
Agent: CS(=O)(=O)O
Solvent: O
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Yield: 94.3 %

Procedure:
A solution of 6.0 g (0.026 moles) of 1-(2,6-dimethylphenyl)-4-methylamino-dihydro-1,3,5-triazin-2-one in 100 ml iPA was prepared with warming. To the warm solution was added 2.0 ml (0.031 moles) of methane-sulfonic acid. The mixture became hot and crystals of white crystalline solid began to form almost immediately. The mixture allowed to cool to room temperature in tap water and filtered. The solution was washed with IPA/Et2O to give 8.00 g of product which was dried overnight at 50°-60° C. in a vacuum. Obtained 8.0 g of 1-(2,6-dimethylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one methanesulfonate after drying.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.C(=O)(O)[O-].[Na+].[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26]>CS(C)=O>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Temperature: 120 °C

Procedure:
A mixture containing 1.0 g of ethyl 2-chloro-5,8-dihydro-8-ethyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate, 0.60 g of sodium bicarbonate, 20 ml of dimethyl sulfoxide, and 0.60 g of 1-acetylpiperazine was heated at 120°C for 1.5 hours with stirring. The dimethylsulfoxide was distilled off in vacuo and the residue was taken up in chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residual solid was recrystallized from a mixture of n-hexane and acetone to yield 1.21 of the product, m.p. 208°- 210°C with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester (example 8 g]) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (example 5 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17]O)[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:55]>O1CCCC1>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:8]3[CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Br:55])[CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ncnn2c(-c3cccc(CO)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnn2c(-c3cccc(CBr)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.1 %

Procedure:
To a solution of {3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]phenyl}methanol (575 mg, 1.29 mmol) and triphenylphosphine (507 mg, 1.93 mmol) in tetrahydrofuran (10 mL) was added carbon tetrabromide (512 mg, 1.55 mmol). The reaction was stirred at rt for 17 h. The mixture was partitioned between water (50 mL) and CH2Cl2 (50 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4), and evaporated. The crude material was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 592 mg (90%) of the desired product, which contained a minor impurity. ES-MS m/z 509.41 [M+H]+, HPLC RT (min) 3.31 min.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(OCC)(=O)C>CC#N.CCCCCC>[C:1]1([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1ccc(C(c2ccccc2)C2CCCNC2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CC#N
Product: CCOC(=O)CN1CCCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a solution of 3-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidine (1.0 g, 3.13 mmol) in MeCN (10 mL) was added triethyl amine (1.3 mL, 9.4 mmol) at rt. After stirring at rt for 15 min, it was cooled to 0° C. and ethyl bromoacetate (0.62 g, 3.71 mmol) was added dropwise. After stirring at rt for 6 h, the solvent was removed under vacuum and the residue was diluted with water, extracted with ethyl acetate, the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afforded the crude product. Column chromatography (SiO2, 10-15% ethyl acetate in hexane) afforded ethyl 2-(3-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)acetate (0.6 g, 48% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:50](Cl)[CH2:51]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:50][CH3:51])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCCCl
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 60 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml dichloromethane were added 20 mg EDC, 13 mg DMAP and 26 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 37 mg MS (ES+): m/e=710.