Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][CH:3]([C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH:25](OC(=O)C)=[O:26]>C1COCC1>[OH:1][N:2]([CH:3]([CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH:25]=[O:26]
Reactant: CCCC#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)NO
Reactant: CC(=O)OC=O
Solvent: C1CCOC1
Product: CCCC#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)N(O)C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.6 %

Procedure:
To a solution of 1-{[2-(hydroxyamino)hept-3-yn-1-yl]sulfonyl}-4-pyridin-2-ylpiperazine (157 mg; 0.45 mmol) in THF (5 mL) was added a solution of acetyl formate (200 mg, prepared as described by Kolle et al., 1983, Helvetica Chimica Acta, 66(8), 2760-8) in THF (2 mL). The reaction mixture was stirred at rt for 5 h and concentrated under reduced pressure. Purification of the crude by flash chromatography on silica (EtOAc:c-Hex, gradient from 50:50 to 100:0) gave the title compound as a white foam (90 mg, 53% yield). HPLC, Rt: 3.04 min (purity: 97.9%). LC/MS, M+(ESI): 381.3, M−(ESI): 379.2. 1H NMR (DMSO-d6) δ: 8.39 (brs, 0.4H), 8.18 (m, 1H), 8.08 (brs, 0.6H), 7.48 (m, 1H), 6.66 (m, 2H), 5.53 (brs, 0.4H), 5.01 (brs, 0.6H), 3.63 (m, 5H), 3.36 (m, 6H), 2.14 (m, 2H), 1.49 (sx, J=7.2 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]([C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:38]([C:41]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([SH:52])=[N:50][N:49]=[N:48]2)=[CH:43][CH:42]=1)([OH:40])=[O:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([C:2]([S:52][C:51]2[N:47]([C:44]3[CH:43]=[CH:42][C:41]([C:38]([OH:40])=[O:39])=[CH:46][CH:45]=3)[N:48]=[N:49][N:50]=2)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(-n2nnnc2S)cc1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Cl)C(=O)c1ccc(OC)cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Sc1nnnn1-c1ccc(C(=O)O)cc1)C(=O)c1ccc(OC)cc1)c1ccccc1
Yield: 93.3 %

Procedure:
33 g of α-chloro-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide and 16 g of 1-(4-carboxyphenyl)-5-mercaptotetrazole were dispersed in 200 ml of chloroform to which was added dropwise 10 ml of triethylamine at room temperature over a period of about 30 minutes. After stirring for 3 hours the chloroform solution was washed with water and concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 41.2 g of α-(4-methoxybenzoyl)-α-[1-(4-carboxyphenyl)-5-tetrazolylthio]-2-chloro-5-dodecyloxycarbonylacetanilide. Yield: 93%. Melting Point: 172° to 174° C.
Reaction SMILES: C1(SC2C=CC(S([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=O)=O)=CC=2)CCCCC1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CN(C)C(=O)C>O>[N:35]1([CH2:34][CH2:33][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(SC2CCCCC2)cc1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CNCCN1CCOCC1
Temperature: 60 °C
Yield: 57 %

Procedure:
The N-[[4-(cyclohexylthio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, from Example 5b (3.34 mmol, 1.145 g), dried 325 mesh K2CO3 (13.4 mmol, 1.84 g), N-(chloroethyl)morpholine (10 mmol, 1.86 g), and N,N-dimethyacetamide (13 mL) were combined and heated at 60° C. under an inert atmosphere for 16 hours, then an additional 4 hours at 80° C. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (100 mL, then 50 mL). The combined organic phases were dried (MgSO4), filtered through a silica plug, concentrated, and subjected to chromatography (ethyl acetate:toluene 1:1), to afford N-[[4-(cyclohexylthio)phenyl]phenyl]sulphonyl]-N-[2-(4-morpholinyl)ethyl]-glycine, 1,1-dimethylethyl ester (954 mg, 57%) as an oil. The structure was verified spectroscopically. MS MH+ calcd. for C24H38N2O5S2 : 499, found: 499. Elemental anal. calc'd for C24H38N2O5S2.0.25H2O: C, 57.29; H, 7.71; N, 5.57. Found: C, 57.32; H, 8.21; N, 5.27.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CCC>[C:19]1([C@@H:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Solvent: CCCCO
Product: C[C@H](Nc1nnc(Cc2ccncc2)c2ccccc12)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 1.273 ml (10 mmol) (S)-1phenylethylamine and 5 ml 1-butanol is stirred for 24 h at 110° C. The reaction mixture is evaporated under vacuum and the residue distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase dried over anhydrous sodium sulfate is evaporated in the RE and then under HV and the residue purified on silica gel by flash chromatography using dichloromethane/methanol (50:1). The product-containing fractions are dissolved in 5 ml methanol, acidified with 0.75 ml 3N methanolic HCl and evaporated under vacuum. After recrystallization of the residue from methanol/acetonitrile, drying of the crystallizate under HV (8 h, 100° C.) and equilibration for 15 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 10.66%; m.p. 190° C. (decomp.); ESI-MS: (M+H)+=341; [a]D20=+42.1±0.8° (c=1.272%, methanol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[NH:13][CH2:12][CH2:11][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCC(c1ccccc1)c1cccc2[nH]ccc12
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)NCCC(c1ccccc1)c1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a stirring solution of 3-(1H-indol-4-yl)-3-phenyl-propylamine (III) (0.40 g, 1.6 mmol) in DCM (15 ml), under N2, was added TEA (0.23 ml, 1.7 mmol). The mixture was cooled to about 0° C. and methyl chloroformate (0.13 ml, 1.7 mmol) in DCM (10 ml) was added dropwise over 15 minutes. The mixture was stirred at room temperature for 30 minutes, quenched by addition of H2O, and stirred for 10 min. The mixture was washed successively with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide [3-(1H-indol-4-yl)-3-phenyl-propyl]-carbamic acid methylester (V) as a white solid (0.48 g, 98% yield).
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]2=[O:22])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:22])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccccc1)N1CCNCC1=O
Yield: 68.3 %

Procedure:
Prepared in the same manner as that described in Example 5, Step 2, using 1-(1-phenylethyl)-4-(tert-butyloxycarbonyl)piperazin-2-one (673 mg, 2.2 mmol), trifluoroacetic acid (4 mL) and CH2Cl2 (40 mL). The crude product was chromatographed on silica gel, eluting with CH2Cl2 :MeOH (90:10), to afford the amine (307 mg, 68%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ1.53 (3H, d, J=7.2 Hz), 2.75-2.94 (2H, m), 2.98-3.07 (1H, m), 3.12-3.21 (1H, m), 3.62 (2H, s), 6.13 (1H, q, J=7.2 Hz), 7.24-7.39 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(N(CC)CC)C.[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:18][CH2:17][C:16]([OH:20])=[O:19]
Reactant: C=CC(=O)O
Reactant: Fc1ccccc1S
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCSc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluorothiophenol (5.0 g, 39 mmol) was dissolved in tetrahydrofuran (50 ml) under a nitrogen atmosphere. Triethylamine (3.94 g, 5.33 ml, 85.8 mmol) was added. Acrylic acid (2.81 g, 2.67 ml, 39 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction solution over 2 h at room temperature. The mixture was stirred at room temperature overnight. 1M Hydrochloric acid (50 ml) was added and the phases were separated. The aqueous phase was washed with ethyl acetate (2×50 ml). The combined organic phases were dried over magnesium sulphate, filtered and concentrated under vacuum. A yellow oil was obtained which solidified upon storage at room temperature. The solid was triturated with hexane, filtered and dried under vacuum. The title compound was isolated as an off-white solid (4.19 g, 20.9 mmol, 54%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]([CH2:12][C:13](OC)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.CCOCC>[OH:14][CH2:13][CH2:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[CH2:11]1
Reactant: COC(=O)CC1CC(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: O=C1CC(CCO)c2ccccc2N1
Yield: 55.4 %

Procedure:
A solution of 11 g (0.05 mol) of methyl (±)-2-oxo-1,2,3,4-tetrahydro-4-quinolineacetate in 50 ml of dioxane is poured dropwise while stirring under an inert atmosphere into a suspension of 2.65 g (0.07 mol) of lithium aluminium hydride in 250 ml of dry ether. The mixture is then heated for 4 h to reflux. After cooling, the reaction is hydrolysed by the slow addition of 10 ml of water with vigorous stirring. The suspension is filtered and the inorganic solid is washed with 20 ml of dioxane. The filtrate is evaporated and the oil obtained is ground in ether, causing it to crystallize. The solid is recrystallized in ethyl acetate. 5.3 g (55%) of (±)-4-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinone, melting point 119°-120° C., are obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[NH:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH3:8].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.O.O.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>[CH2:7]([O:9][C:10]([C:12]1[NH:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:11])[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccc(Br)[nH]1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2)[nH]1
Yield: 67.7 %

Procedure:
Na2CO3 (97.5 mg, 0.92 mmol) was added to a stirred solution of 5-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg, 0.46 mmol) in toluene: H2O (5:1, 11 mL). Pd (PPh3)4 (53 mg, 0.046 mmol) and phenylboronic acid (84.3 mg, 0.7 mmol) were then added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to get the residue. The residue obtained was purified by column chromatography (using silica gel of 60-120 mesh and 5% EtOAc in Hexane as eluent) afford 67 mg (67.95% yield) of 5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 9.4 (s, 1H), 7.64 (d, 2H), 7.48 (t, 2H), 7.36 (d, 11H), 7.0 (s, 1H), 6.58 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]5)=[CH:17][CH:18]=4)[CH2:13]C[C:11]=3[CH:10]=2)[O:3]1.BrC1C=CC2C3C(=CC(Br)=CC=3)C(=[O:48])C=2C=1>>[CH3:29][C:26]1([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24][B:23]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[C:21](=[CH:22][C:9]([B:4]5[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:1])([CH3:32])[O:3]5)=[CH:10][CH:11]=4)[C:13](=[O:48])[C:14]=3[CH:15]=2)[O:27]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Product: CC1(C)OB(c2ccc3c(c2)C(=O)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C

Procedure:
Followed the procedure used to prepare 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane, except that 2,7-dibromo-9-fluorenone was used instead of 2,7-dibromo-9,10-dihydro-phenanthrene.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])(C)(C)C.[Cl:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][N:17]=1>C(OCC)C>[Cl:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: BrCCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: Clc1cc(CCc2ccccc2)nc(Cl)n1
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.6 mL of (2-bromoethyl)benzene in 70 mL ethyl ether at −70° C. was added 41.5 mL of tert-butyllithium. The mixture was slowly allowed to warm to −30° C. over 2 h, then cooled to −60° C. and treated with 5.0 g of 2,4-dichloropyrimidine The reaction was again slowly allowed to warm to −30° C. over 2 h, then quenched by the addition of 1.94 mL of acetic acid and 0.30 mL of water in 5 mL tetrahydrofuran. The mixture was treated with 7.6 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in 25 mL THF and warmed to room temperature. The reaction was cooled to 0° C. and 13.4 mL of ice-cold 3 M NaOH was added to the mixture. After 5 minutes, the organic layer was separated and dried over sodium sulfate. The solvent was evaporated and the crude residue was chromatographed (2% to 10% EtOAc in hexanes) to give 4.0 g of 2,4-dichloro-6-phenethylpyrimidine.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:31]([CH3:33])[CH3:32])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Br:30])[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.O>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Br:30])[N:8]2[CH2:2][CH2:3][N:4]([CH:31]([CH3:32])[CH3:33])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 41.9 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylicacid(2-hydroxyethyl)-isopropylamide (379) (1.0 g, 1.873 mmol) and triphenyl phosphine (1.717 g, 6.554 mmol) in dichloromethane (120 mL), diisopropyl azodicarboxylate (1.114, 5.618 mmol) was added over 10 h (dilution 0.19 M; rate 3 ml/h) at 0° C. The reaction was monitored by silica thin layer chromatography (3% methanol in dichloromethane; Rf=0.4). After completion of the reaction, 50 mL water were added and the mixture was extracted with dichloromethane (2×100 mL). The organic part was dried over sodium sulphate and concentrated. The resulting crude product was column purified (using amine bound silica) to get 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (0.406 g, 41.95%) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]([CH3:10])([CH3:9])[C:7]#N)[CH2:3]1.[OH-:12].[Na+].C([OH:16])C>O>[F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]([CH3:10])([CH3:9])[C:7]([OH:16])=[O:12])[CH2:3]1
Reactant: CCO
Reactant: CC(C)(C#N)C1CC(F)(F)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C(=O)O)C1CC(F)(F)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of Intermediate 226A (150 mg, 0.942 mmol) in ethanol (10 mL) and H2O (10 mL) was added a 10% aqueous solution of NaOH (10 mL, 0.942 mmol) and the reaction mixture was stirred at 90° C. for 12 h. The reaction was then concentrated and the pH of the resultant residue was adjusted to 4 with a 1.5 N aq. solution of HCl and then extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure to afford Intermediate 226B as a yellow sticky liquid (100 mg, 60%). 1H NMR (400 MHz, chloroform-d) δ ppm 12.30 (bs, 1H), 2.40-2.57 (m, 5H), 1.23 (s, 6H).
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=1.[CH3:21][C:22]([CH3:24])=O>>[C:5]([C:22]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=1)([CH3:24])[CH3:21])#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)=O
Reactant: COC(=O)CCCc1ccc(N)cc1
Product: COC(=O)CCCc1ccc(NC(C)(C)C#N)cc1
Yield: 96 %

Procedure:
TMSCN (1.44 mL, 10.8 mmol) was added to a mixture of the compound 27 (0.7 g, 3.6 mmol), acetone (1.60 mL, 21.6 mmol) and 12 (50 mg, 0.4 mmol) with stirring. The reaction mixture was stirred at 50° C. for 0.5 h. The reaction was concentrated in vacuo. The residue was diluted with aq Na2SO3 and extracted with ethyl acetate. The combined organic layers were washed with aqNa2SO3 and brine, dried over Na2SO4 and concentrated to dryness to give compound 28 (0.9 g) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.07 (d, 2H, J=8.3 Hz), 6.87 (d, 2H, J=8.3 Hz), 3.66 (s, 3H), 2.58 (t, 2H, J=7.4 Hz), 2.32 (t, 2H, J=7.4 Hz), 1.85-1.95 (m, 2H), 1.68 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9].O>C(O)C>[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:3][N:2]([CH3:4])[CH3:1])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CN(C)N
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNN(C)C)C(=O)c1cc(F)c(F)c(F)c1F

Procedure:
3.1 g of 1,1-dimethylhydrazine are added dropwise to a solution of16 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy-acrylate in 60 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 60 ml of H2O are added, the mixture is cooled with ice and the precipitate is filtered off with suction and washed with water/ethanol (1:1). 12.9 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2,2-dimethylhydrazino)-acrylate of melting point 81° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13](=O)[CH2:14][CH3:15].Cl>C(O)(C)C.C(OCC)(=O)C>[CH2:14]([CH:13]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:9](=[O:11])(=[O:10])[NH:12]1)[CH3:15]
Reactant: CCC=O
Reactant: CNc1ccncc1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCC1NS(=O)(=O)c2cnccc2N1C
Temperature: 50 °C

Procedure:
A solution of 0.5 g of 4-methylaminopyridine-3- sulfonamide (Preparation 12) and 0.9 cm3 of propionaldehyde in 5 cm3 of isopropanol, to which 3 drops of a saturated solution of hydrochloric acid in ethyl acetate have been added, is heated for 3 hours at 50° C. The solvent is then removed under partial vacuum and the residue obtained is recrystallized several times from a chloroform/petroleum ether (1/3) mixture.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][O:19][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Reactant: COc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)c1
Yield: 62.4 %

Procedure:
Essentially the same procedure was used to make compound 25s as was used for compound 18s (Example 16), with compound 51 (Example 10; 52 mg, 0.2 mmol), 3-methoxyphenol (0.032 ml, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), and THF (1 ml). The crude residue was purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford the title compound as a colourless oil (46 mg; 62%). Analyses were performed on the free base, and the free base was converted to the HCl salt for testing.
Reaction SMILES: C1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)CC1.[C:30]([BH3-])#[N:31].[Na+].C=O.[C:36](O)(=O)C>C(#N)C.C(O)(=O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:17]2([CH2:16][O:15][CH:13]([C:11]3[CH:12]=[C:4]([C:30]#[N:31])[CH:5]=[C:6]4[C:10]=3[NH:9][N:8]=[CH:7]4)[CH3:14])[CH2:22][CH2:21][N:20]([CH3:36])[CH2:19][CH2:18]2)=[CH:28][CH:27]=1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(C2CC2)cc2cn[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(C#N)cc2cn[nH]c12
Reaction time: 0.08 h

Procedure:
To a suspension of (±)-5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (21.8 mg, 0.055 mmol) and sodium cyanoborohydride (17.4 mg, 0.277 mmol) in acetonitrile (1 mL) at 0° C. was added formalin (0.041 mL). The reaction was treated with 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added. The ice bath was removed and stirring continued for another hour. The reaction was diluted with diethyl ether and washed with 1 M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. It was then purified by preparative HPLC to give 7.8 mg (55.7%). LC/MS (HPLC method 3): tR=1.742 min, 393.07(MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-trifluoromethyl-benzene following the procedure of Example 478: MS (ESI) m/z 552.