Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si](C)(C)C)=[CH:17][C:16]=1[F:25].[I:27]Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:27])=[CH:17][C:16]=1[F:25]
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2-(2-fluoro-4-trimethylsilanylphenylamino)-6-formylamino methyl-nicotinic acid methyl ester (10.3 g, 27.4 mmol) in DCM (275 mL) at 0° C. was added dropwise iodine monochloride as a solution in DCM (54.9 mL, 1M, 54.9 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was washed with aqueous sodium metabisulfite (100 mL, 0.5 M) and the aqueous layer extracted twice with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an orange gum (11.6 g, 100%). LCMS (Method B): RT=3.72 min, M+H+=430.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N)CCCCCCCCCCC.C=CCCCCCCCCCC>>[CH2:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CNC
Reactant: CCCCCCCCCCCCO
Agent: C=CCCCCCCCCCC
Agent: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCN(C)C
Reaction time: 0.01 h

Procedure:
50 grams of the said catalyst is charged into a reactor tube, for example as shown and described in O.S. II page 389, and the tube is heated preferably to 360° C. and it is well to condition the tube with a flow of air (as about 500 ml. per minute) for a period of hours. The air flow then is discontinued, and approximately two milli-equivalents of dimethyl amine and 1 milli-equivalent of dodecyl alcohol, per minute, are simultaneously charged into the reactor tube. The outflow is essentially 95% dodecyl amine and 5% dodecene, as determined by G.L.C. If any dodecyl alcohol is present in the product, this indicates that the through-put was too fast, and the residence time of the reacting materials in the tube or column may be set at about 30 seconds.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35].C([Li])CCC>O1CCCC1.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([N:32]1[CH2:33][CH2:34][O:30][C:31]1=[O:35])=[O:15]
Reactant: O=C1NCCO1
Reactant: O=C(O)/C=C/c1ccc2ccccc2c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc2ccccc2c1)N1CCOC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (E)-3-(2-naphthyl)prop-2-enoic acid (10 g, 0.05 mole) at −78° C., was added triethylamine (8.42 ml, 0.06 mole) and pivaloyl chloride (7.5 ml, 0.06 mole). Stirring was continued for 1 hour. To a stirred solution of oxazolidinone (5.14 g, 0.06 mole) in dry tetrahydrofuran (200 ml) at −78° C. was added slowly n-butyl lithium (1.6M in hexanes, 38 ml, 0.06 mole). Stirred for 1 hour. The suspension of the mixed anhydride was transferred into the oxazolidinone anion by means of a canula maintaining the temperature below −60° C. The resulting reaction mixture was stirred for 2 hours. Water was added cautiously and the reaction extracted with ethyl acetate. The solvent was washed with brine, dried and evaporated to dryness in-vacuo. Chromatography on flash silica using ethyl acetatehexane (1:1) gave 3-[(E)-3-naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one as a white solid, M/e 268 (M+H).
Reaction SMILES: [OH-].[K+].[I-].[NH2:4][N+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O.ClCCl>[F:11][C:12]([F:20])([F:21])[C:13]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: N[n+]1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nn2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.3 %

Procedure:
A solution of 2.1 g (38 mmol) of KOH in 20 ml of water and then 6.7 g (30 mmol) of 1-aminopyridinium iodide are added to a solution of 2.5 g (15 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in 25 ml of dichloromethane. After stirring at ambient temperature for 5 h, water is added and the reaction medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl 2-trifluoromethylpyrazolo[1,5-α]pyridine-3-carboxylate are obtained in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].ClCCl>O>[C:31]([O:22][C:20]1[CH:19]=[CH:18][C:17]([Cl:23])=[C:16]([N:3]2[C:2]([NH2:1])=[C:6]3[C:7](=[O:15])[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]3=[N:4]2)[CH:21]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1cc(O)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc(Cl)c(-n2nc3c(c2N)c(=O)[nH]c2ccccc23)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-amino-2-(2-chloro-5-hydroxyphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (65 mg), triethylamine (31 μl), acetyl chloride (15 μl) and dichloromethane (1.7 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and chloroform-hexane was added to the residue. The precipitated solid was collected by filtration to obtain the target compound (52 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:9][CH2:8]1.C(N(CC)CC)C.[F:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>O1CCCC1>[CH:7]1([N:6]([CH2:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[Si:2]([CH3:15])([CH3:14])[CH3:1])[C:33]([C:25]2[C:26]([CH:30]([F:32])[F:31])=[N:27][N:28]([CH3:29])[C:24]=2[F:23])=[O:34])[CH2:8][CH2:9]1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: C[Si](C)(C)c1ccccc1CNC1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc(C(F)F)c(C(=O)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Yield: 66.1 %

Procedure:
To 175 mg (0.80 mmol) of N-[2-(trimethylsilyl)benzyl]cyclopropanamine in 5 ml of dry tetrahydrofurane was added 0.234 ml (1.68 mmol) of triethylamine, followed by a solution of 187 mg (0.88 mmol) of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride in 3 ml of tetrahydrofurane. The reaction mixture was stirred under reflux for 3 hours. After cooling down, the reaction mixture was filtered, and the filtrate was evaporated under vacuum. The residue was dissolved in ethyl acetate/water. The aqueous phase was further extracted with ethyl acetate. The combined organic phase were dried and evaporated under vacuum to give 209 mg of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:11](=[O:13])[CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)CC(OCC)=O)=[CH:17][CH:16]=1.P(Cl)(Cl)Cl>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[NH:10][C:11](=[O:13])[CH:12]=2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1NNC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: ClP(Cl)Cl
Product: COc1ccccc1-n1[nH]c(=O)cc1-c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 51.7 %

Procedure:
To a mixture of N′-(2-methoxyphenyl)acetohydrazide (2.90 g, 16.09 mmol) and ethyl 3-(4-chlorophenyl)-3-oxopropanoate (3.65 g, 16.09 mmol) in 10 mL of DCE was added drop wise phosphorus trichloride (1.41 mL, 16.09 mmol). The mixture was heated to 50° C. and all solids dissolved. After 2 hrs at 50° C. the mixture was cooled to RT and the ppt was collected by filtration and washed with water and EtOAc and dried to give 2.50 g (49%) of a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:36][CH2:35][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[CH3:34]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](N)CO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](C)CO)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (2.25 g, 5.03 mmol) synthesized in Example (106c) was dissolved in methanol (50 mL), and D-alaninol (0.70 mL, 8.97 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (3.05 g, 11.02 mmol) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with ethyl acetate (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80%-100%) to afford the desired compound (1.95 g, yield 75%) as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]([N:27]=C=O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[C:19]([NH:27][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([NH:45][C:41]1[CH:42]=[CH:43][C:44]2[N:32]([CH2:30][CH3:31])[C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:18])=[O:7])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)NC(=O)c3ccccc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 59% purity by LC/MS. MS(ESI+): m/z=498.4.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]#[N:20])[N:18]=2)=[O:13])=[C:7]([C:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=2)[CH:6]=1)C.[OH-].[K+].C(O)(C(F)(F)F)=O>CCO>[C:19]([C:17]1[N:18]=[C:14]([C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[CH:6][C:7]=2[C:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=2)=[O:13])[NH:15][CH:16]=1)#[N:20]
Reactant: CCOC(=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C(=O)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 60 °C
Yield: 84.4 %

Procedure:
To a solution of 4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-benzoic acid ethyl ester (50 mg, 0.13 mmol) in 1 mL of EtOH was added a 2 N aqueous solution of KOH (0.20 mL, 0.10 mmol) and the mixture heated to 60° C. for 6 h. The pH was adjusted to 2 with 2 N aq TFA and the title compound was purified by RP-HPLC eluting with a linear gradient of 30% to 50% acetonitrile in 0.1% TFA/H2O over 10 min on a C18 column giving 40 mg (87%) of a white solid. 1H-NMR (CD3OD, 400 MHz): δ 8.48 (d, J=8.6 Hz, 1H), 8.04 (s, 1H), 7.96 (dd, J=8.6, 2.0 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 5.85 (m, 1H), 2.40-2.32 (m, 2H), 2.17-2.13 (m, 2H), 1.66 (t, J=6.3 Hz, 2H), 1.15 (s, 6H). Mass spectrum (APCI, m/z): Calcd. for C20H20N4O3, 363.2 (M-H), found 363.4.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:16][CH2:17][CH2:18][O:19][CH3:20])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:12]([C:11](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])[C:10]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15])(=[O:13])[CH3:14]
Reactant: O=Cc1ccccc1F
Reactant: COCCOC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COCCOC(=O)C(=Cc1ccccc1F)C(C)=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
10 g (80 mmol) of 2-fluorobenzaldehyde are dissolved in 200 ml of isopropanol with 13 g (80 mmol) of 2-methoxyethyl acetoacetate. A freshly prepared solution of 1.0 ml of piperidine and 0.5 ml of glacial acetic acid in 10 ml of isopropanol is added to this solution and it is stirred overnight at 40° C. The mixture is concentrated, the residue is taken up in toluene, the solution is concentrated again and the residue is purified by filtration on 300 ml of silica gel (eluent: toluene/ethyl acetate 100:1-10:1) to give 15 g of the target compound as a yellow oil which is immediately reacted further.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>CCO>[CH:18]1([CH2:24][NH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)-2,2-dimethylpropanamide (158 mg, 0.658 mmol) and cyclohexylmethylamine (0.100 mL, 0.790 mmol) were stirred in 3 mL of EtOH containing triethylamine (0.140 mL, 0.987 mmol) at 75° C. for 24 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. Yield: 217 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 0.98-1.09 (m, 2H), 1.17-1.28 (m, 3H), 1.31 (s, 9H), 1.65-1.73 (m, 2H), 1.74-1.80 (m, 2H), 1.82-1.84 (m, 1H), 1.85-1.88 (m, 1H), 3.15 (dd, J=6.64, 5.47 Hz, 2H), 6.83 (d, J=9.37 Hz, 1H), 7.23 (br.s, 1H), 7.82 (dd, J=9.18, 2.54 Hz, 1H), 8.10 (d, J=2.54 Hz, 1H), 8.11-8.13 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH3:18])[N:12]=1.CCN(C(C)C)C(C)C.CCO>O>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[CH:14]=[C:13]([CH3:18])[N:12]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 70 °C
Reaction time: 72 h
Yield: 59.1 %

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (1.98 g, 16.07 mmol), 2,4-dichloro-6-methyl-pyrimidine (2.62 g, 16.07 mmol), DIPEA (5.7 mL, 32.15 mmol) and anhydrous EtOH (50 mL) was stirred at 70° C. under N2 for 3 d. The reaction mixture was cooled and poured into water (ca. 700 mL). The reaction was stirred at RT overnight until solid precipitated out. The solid was filtered, washed with additional water and pumped dry under high-vacuum to afford 2.37 g (59%) of 189 as a solid: 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.08 (s, 1H), 7.04 (br s, 1H), 5.93 (br s, 1H), 2.27 (s, 3H), 1.93 to 1.84 (m, 1H), 0.96-0.88 (m, 2H), 0.70-0.64 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH2:19].[Br:20]N1C(=O)CCC1=O>CS(C)=O>[Br:20][CH2:1][CH:2]([OH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:20][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][OH:19]
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: O
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCC(Br)CO
Product: CCCCCCCCCCCCCCCCC(O)CBr
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
While stirring vigorously 15.12 g (60 mmoles) of 1-octadecene in 300 ml of DMSO containing 2.7 g of water, 21.36 g (120 mmoles) of N-bromosuccinimide was added over a period of 40 minutes. The mixture was stirred at room temperature for 100 minutes, poured into a cold water and extracted with ether. The extract was washed with water, dried and concentrated. The residue was purified by recrystallization and silica gel chromatography to give 10.7 g of 1-bromo-2-hydroxyoctadecane (m.p. 53.5°-54.5° C.), 3.0 g of 2-bromo-1-octadecanol (m.p. 39°-39.5° C.) and 3.78 g of a mixture of these compounds.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:27].C[O:29][C:30](=[O:40])[CH:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)O>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([OH:40])=[O:29]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(O)ccc2c1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1

Procedure:
The title compound was prepared from 1-bromo-6-(2-butyl-benzofuran-3-carbonyl)-naphthalen-2-ol, and 3-phenyllactic methyl ester, in substantially the same manner, as described in Example 5, and was obtained as a white solid, mp 165-167° C.; MS m/e 570 (M+);
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:24][C:25](=[O:26])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(CBr)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 146.97 mg (0.709 mmol) of 2-bromo-1-(tetrahydropyran-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16]CCCCC.[Si](C=[N+]=[N-])(C)(C)C>CO.C1C=CC=CC=1>[CH3:16][O:11][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of the N-tert-butoxycarbonylproline (6.00 g, 0.0279mol) in MeOH:benzene (1:4, v/v) was added dropwise 2.0 M-n-hexane solution of TMSCHN2 (16.7 mL, 0.0334mol) at room temp. After the resulting solution was stirred for 1 hr at room temp, the mixture was evaporated off in vacuo to afford 6.39 g (100%) N-tert-butoxycarbonylproline methyl ester as a yellow syrup. 1H-NMR (CDCl3) δ 1.41 (s, 9H), 1.85–1.98 (m, 4H), 2.21–2.28 (m, 2H), 3.72 (s, 3H), 4.29 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.[NH2:21][NH2:22]>>[F:1][C:2]1[CH:10]=[C:6]2[C:5]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:21][NH:22][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1C(=O)c1ccc(F)cc1
Reactant: NN
Solvent: O
Product: O=c1[nH]nc(-c2ccc(F)cc2)c2ccc(F)cc12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-fluoro-2-(4-fluorobenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[CH:21])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9])=C.Cl.O1CCOCC1>CO.C1COCC1>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[CH:21])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9]
Reactant: C#CCn1c(C(=O)NOCCOC=C)c(Nc2ccc(I)cc2F)c2cnccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C#CCn1c(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-prop-2-ynyl-1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (35.0 mg, 0.067 mmol) in anhydrous MeOH (6.7 mL) and anhydrous THF (3.4 mL) under N2 was added 4 M HCl in dioxane (50 μL, 0.20 mmol, 3.0 eq), and the reaction mixture was stirred at room temperature. After 3 h the solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and MeOH (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Trituration from DCM-hexane afforded the title compound as a yellow solid (32.7 mg, 98.5%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.58 (d, J=0.82 Hz, 1H), 8.36 (d, J=5.93 Hz, 1H), 7.79-7.62 (m, 2H), 7.60-7.47 (m, 1H), 7.30-7.15 (m, 1H), 6.34-6.15 (m, 1H), 5.33 (s, 2H), 4.77 (broad s, 1H), 3.84 (t, J=4.54 Hz, 2H), 3.61-3.50 (m, 2H), 3.42-3.34 (m, 2H); LC-MS (method E): [M+H]+=495.1, RT=3.54 min.