Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].N1CCCC1.I[C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>[Cu]I>[C:1]([NH2:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCC#CC#CCCCCCC#CI
Reactant: C#CCCCCCCCCC(N)=O
Agent: [Cu]I
Solvent: C1CCNC1
Product: CCCCCCCCC#CC#CCCCCCC#CC#CCCCCCCCCC(N)=O
Reaction time: 48 h

Procedure:
CuI (0.126 g, 0.66 mmol) and 10-undecynoic acid amide (0.29 g, 1.59 mmol) were added to a flask and inerted with nitrogen. Pyrollidine (5 mL) was then added. In a separate flask 1-Iodo-nonadeca-1,8,10-triyne (0.5 g, 1.3 mmol) was mixed with pyrollidine (5 mL) and subsequently added slowly to the amide solution. The reaction mix was left in darkness under nitrogen for 48 hours, then quenched with aqueous 1M NH4Cl (10 mL), and worked up with CH2Cl2 and 1 M HCl. The organic was dried over anhydrous MgSO4. Organic products were concentrated by rotary evaporation, although polymer formed, decreasing yield. Hexanes trituration removed unreacted 1-Iodo-nonadeca-1,8,10-triyne. Desired product was obtained by several crystallizations from hexanes/ethyl acetate, again under dark conditions. All handling of the solid was done under red light. Final product triaconta-10,12,19,21-tetraynoic acid amide was made up of white crystals (0.377 g, 0.86 mmol) and was stored frozen (liquid nitrogen) in methylene chloride. 65% yield; 1H NMR (CDCl3) δ: 5.31 (s, 2H, NH2), 2.22-2.26 (m, 10H, CH2—C≡C & CH2—CO), 1.58-1.66 (quin, 2H, J=7, CH2—C—CO), 1.45-1.56 (m, 8H, CH2—C—C≡C), 1.28-1.4 (m, 20H, C—CH2—C), 0.86-0.91 (t, 3H, CH3); 13C NMR (CDCl3) δ 175.69, 77.98, 77.84, 77.34, 65.69, 69.45, 65.37, 57.68, 53.63, 38.37, 38.35, 33.80, 32.97, 32.92, 32.03, 29.34, 29.27, 29.07, 28.94, 28.55, 28.47, 28.26, 28.26, 28.06, 27.17, 25.67, 22.86, 19.39, 19.32 14.30. MS (ESI) [M+H]+ calc. 436.3574 found 436.3560.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C.O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a suspension of dimethyl malonate (9.77 mL, 85.07 mmol, 1.2 eq) in DMF (100 mL) and K2CO3 (29.36 g, 212.76 mmol, 3.0 eq) was added 1-fluoro-4-nitrobenzene (7.51 mL, 70.91 mmol, 1.0 eq) at RT and the mixture was stirred for 16 h at 70° C. The reaction mixture was cooled to RT and diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate layers were collected, washed with cold water (2×50 mL), brine (50 mL), dried over sodium sulfate and evaporated under vacuum. The crude product was washed with n-pentane (50 mL) to get dimethyl 2-(4-nitrophenyl)malonate 14 g, 78%) as pale yellow solid (TLC system: EtOAc/PE (3:7), Rf: 0.50).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[CH2:12]([O:19][C:20]([C:22]1[C@H:23]2[CH2:31][CH:30]=[C:29]([CH3:32])[C@@H:24]2[C@@H:25]([OH:28])[O:26][CH:27]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([O:19][C:20]([C:22]1[C@H:23]2[CH2:31][CH:30]=[C:29]([CH3:32])[C@@H:24]2[C@H:25]([O:28][C:10](=[O:11])[NH:9][CH3:8])[O:26][CH:27]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1=CC[C@@H]2C(C(=O)OCc3ccccc3)=CO[C@H](O)[C@@H]12
Reactant: CN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OCc2ccccc2)[C@H]2CC=C(C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
9.2 ml of triethylamine and 2.4 ml of methylisocyanate were added to an acetonitrile solution containing 4.98 g of (1S,4aS,7aR)-1-hydroxy-7-methyl-1,4a,5,7a-tetrahydrocyclopenta [c]-pyrane-4-carboxylic acid benzyl ester followed by stirring for 1 hour at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,7aR)-7-methyl-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta [c]-pyrane-4-carboxylic acid benzyl ester of 5.10 g (yield: 86%). The physicochemical properties of this compound are shown below.
Reaction SMILES: N[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BrH:13].N([O-])=O.[Na+]>O>[C:4]1([CH2:3][C@@H:2]([Br:13])[C:10]([OH:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Br
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](Br)Cc1ccccc1
Temperature: -5 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
Mix D-phenylalanine (186.4g, 1.128mol) and 49% hydrobromic acid (372.8g), cool to -5° C. and add, by dropwise addition, a solution of sodium nitrite (77.9g) in water (565mL) over a period of about 1 hour (vigorous gas evolution). Stir at -5° C. to 0° C. for 4 hours, extract into ethyl ether (3×1L), dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (5% acetic aci/95% methylene chloride) and distillation to give 3-phenyl-2(R)-bromopropionic acid (112g, 43%); bp 128°-135° C. @0.25 torr.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1Br.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)=[O:18]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(N2CCC(O)CC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(N2CCC(O)CC2)cc1-c1ccccc1
Temperature: 90 °C
Yield: 91.6 %

Procedure:
A mixture of 2-bromo-4-(4-hydroxy-piperidin-1-yl)-benzoic acid methyl ester (1.2 g, 3.82 mmol), phenylboronic acid (800 mg; 6.56 mmol), potassium phosphate, tribasic, mono-hydrate (1.3 g, 10.7 mmol), and tetrakis(triphenylphosphine)palladium (500 mg, 0.433 mmol) in 1,2-dimethoxyethane (25 mL) and water (1 mL) is heated to 90° C. under a nitrogen atmosphere for 24 h. The mixture is concentrated and partitioned between ethyl acetate and water. The solvent layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified on silica (120 g) eluting with a gradient of 0% to 100% ethyl acetate in heptane to provide the desired product (1.09 g, 92%) as a gummy residue. LC-ES/MS m/z 312.0 (M+1)
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])#[N:2]
Reactant: COc1cc(CCl)c(CCNC(=O)C(F)(F)F)cc1OC
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC#N)c(CCNC(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
In a three-necked flask stir, at ambient temperature, a suspension of sodium cyanide (9.8 g, 200 mmoles) in 160 mL of DMSO. Add to the suspension, dropwise, a solution of N-{2-[2-(chloromethyl)-4,5-dimethoxyphenyl]ethyl}-2,2,2-trifluoroacetamide (26 g, 798 mmoles) in 80 mL of DMSO. After being in contact for 1 hour 30 minutes at ambient temperature, hydrolyse the mixture using 300 mL of water and extract the mixture with dichloromethane (3×150 mL). Combine the organic phases and wash them with 10% aqueous solution of NaOAc (150 mL) and saturated aqueous NaCl solution (4×150 mL), then dry them over MgSO4 and carry out drying in vacuo. The product obtained is recrystallised from toluene (66 mL) to obtain 12.8 g of a white powder corresponding to the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH3:22])[CH2:19][C:20]#C)[N:15]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:4])([CH3:3])[CH3:2].C[NH:29]CC#N.CNCC#C>>[C:23]([C:7]1[CH:8]=[C:9]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][C:20]#[N:29])[CH3:22])[N:15]=2)[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]=1[OH:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: C#CCN(C)CCc1coc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Reactant: CNCC#N
Agent: C#CCNC
Product: CN(CC#N)CCc1coc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 36 %

Procedure:
The experimental protocol used is identical to that described for the compound of Example 26, methylaminoacetonitrile being used as starting product in place of the N-methylpropargylamine. A white solid is obtained with a yield of 36%. Melting point: 165-167.8° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=O.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[C@@H:18]1([NH:28][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: N#Cc1ccc(Oc2cccc(C=O)c2)cc1
Product: N#Cc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 50A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: COC1C=C(OC2C=CC(O)=CC=2)C2CC(C3C=CC(OC)=CC=3)CCC=2C=1.Cl.ClCCN(C(C)C)C(C)C.[CH:40]([N:43]([CH:74]([CH3:76])[CH3:75])[CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[C:63]3[CH2:62][CH:61]([C:64]4[CH:69]=[CH:68][C:67]([O:70]C)=[CH:66][CH:65]=4)[CH2:60][CH2:59][C:58]=3[CH:57]=[C:56]([O:72]C)[CH:55]=2)=[CH:49][CH:48]=1)([CH3:42])[CH3:41]>>[CH:74]([N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[C:63]3[CH2:62][CH:61]([C:64]4[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=4)[CH2:60][CH2:59][C:58]=3[CH:57]=[C:56]([OH:72])[CH:55]=2)=[CH:49][CH:48]=1)([CH3:75])[CH3:76]
Reactant: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCCN(C(C)C)C(C)C)cc4)c3C2)cc1
Agent: CC(C)N(CCCl)C(C)C
Agent: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(O)cc4)c3C2)cc1
Agent: Cl
Product: CC(C)N(CCOc1ccc(Oc2cc(O)cc3c2CC(c2ccc(O)cc2)CC3)cc1)C(C)C
Yield: 22.3 %

Procedure:
Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and (2-chloroethyl)diisopropylamine hydrochloride according to an analogous synthetic method to Preparation Example 40, diisopropyl{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenoxy}ethyl}amine (408 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (86 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:12]1=[O:13].[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CC(C)=O>[C:24]1([N:14]2[C:12](=[O:13])[C:11]([CH2:10][CH2:9][CH2:8][CH3:7])([CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:16](=[O:17])[N:15]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC1(COC(=O)C(C)(C)C)C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Yield: 5 %

Procedure:
Potassium carbonate (2.26 g, 0.016 mole) was suspended in an acetone (125 ml) solution of phenylbutazone and the suspension was refluxed overnight. The next day pivalyloxymethyl chloride (4.99 g, 0.033 mole) was added to the resulting solution and the solution was refluxed overnight. The suspension was cooled and filtered; the residue (2.00 g, 83%) was potassium chloride. The filtrate was concentrated in vacuo and the residue was suspended in ether, then filtered. The residue was washed with ether until the washings did not contain any product by TLC. The residue from the ether suspension was the potassium salt of phenylbutazone (2.25 g, 20%). The ether was then concentrated in vacuo and the residue was absorbed on silica gel and chromatographed on neutral silica gel (CC-7, Mallinckrodt) using petroleum ether bp 30-60° C - ether (1:1) as the eluent to give two fractions. The first fraction (Rf 0.46, silica gel, heptane-ether, 1:1) was crystallized from heptane-petroleum ether bp 30-60° C, 1:1 to give 0.63 g (mp 116- 117° C, 5% yield) of 1,2-diphenyl-4-butyl-4-pivalyloxymethyl-3,5-pyrazolidinedione. nmr (CDCl3) δ 4.40 (S, 2, ##STR11##
Reaction SMILES: Cl.C(O[C:5](=[NH:42])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[N:15]([CH:39]=[CH:40][N:41]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=4)[C:20]=3[CH3:38])[N:18]=2)=[CH:8][CH:7]=1)C.[CH2:43](N)[CH2:44][NH2:45]>CO>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]3[N:18]=[C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([C:5]5[NH:45][CH2:44][CH2:43][N:42]=5)=[CH:11][CH:10]=4)[C:14]4[N:15]([CH:39]=[CH:40][N:41]=4)[CH:16]=3)[C:20]=2[CH3:38])=[O:37])=[CH:32][CH:31]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CCOC(=N)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn3ccnc23)cc1
Reactant: NCCN
Agent: Cl
Solvent: CO
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn2ccnc2c(Nc2ccc(C3=NCCN3)cc2)n1
Temperature: 60 °C
Yield: 35.4 %

Procedure:
4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidic acid ethyl ester hydrochloride (150 mg; 0.26 mmol) is dissolved in methanol (5 mL) in a glass pressure reaction vessel, and ethylenediamine (100 mg; excess) is added. The reaction is heated to 60° C. for 16 hr then concentrated in vacuo. The oil is dissolved in 2 mL CH2Cl2 and diethyl ether (20 mL) is added to precipitate out 4-tert-butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide as a light tan solid (100 mg). Gradient silica flash chromatography using (90:9:1) (CH2Cl2:methanol:ammonium hydroxide) as the eluent provides the pure material as a white solid (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:30]([CH3:32])[CH3:31]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:30]([CH3:32])[CH3:31])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (15.33 g), potassium carbonate (7.50 g) and 2-iodopropane (5.43 ml) in N,N-dimethylformamide (150 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separated solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-chlorophenyl)-6-isopropoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (13.54 g) as a white crystal.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][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][CH3:16].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:20](=[O:21])([O:22][CH2:23][CH3:24])[O:17][C:1](=[O:18])[CH2:2][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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC(=O)OCC

Procedure:
Palmitic acid and ethyl chloroformate are reacted with methylene chloride in a molar ratio of 1:1 in the presence of dry sodium carbonate. Inorganic material is filtered off, and the resulting filtrate is used directly in the reaction.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C1COCC1>[CH3:10][S:11]([O:3][C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8])(=[O:13])=[O:12]
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H](CC(=O)O)C(=O)O
Yield: 99 %

Procedure:
A solution of 8.04 g (0.060 mol) of (S)-malic acid and 9.2 mL (0.120 mol) of methanesulphonyl chloride in 60.0 mL of THF was refluxed for 10 hours. After cooling, the solution was vacuum evaporated to dryness to obtain 12.60 g (99%) of the title compound. H-NMR in DMSO-d6: δ 2.41 (3H, s, CH3SO3), 2.90 (2H, m, CH2), 5.47 (1H, t, CHOSO2).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([CH3:41])[CH:25]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38](=[NH:40])[NH2:39])=[CH:34][CH:33]=4)[C:26]([O:28]CC)=[O:27])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH:42]([O-:44])=[O:43]>ClCCl.CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([CH3:41])[CH:25]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH2:40])=[CH:36][CH:37]=4)[C:26]([OH:28])=[O:27])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3].[CH:42]([O-:44])=[O:43]
Reactant: CCOC(=O)C(Cc1ccc(C(=N)N)cc1)N(C)C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C
Agent: O=C[O-]
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C(Cc1ccc(C(=N)N)cc1)C(=O)O
Yield: 90 %

Procedure:
The reaction takes place analogously to the procedure described in Example 30 starting from ethyl 2-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carbonyl-(methylamino)}-3-(4-amidinophenyl)-propionate (Example 29, 1.7 mmol). The product is obtained by crystallisation from dichloromethane/methanol. Yield: >90%; melting point: 255° C.; mass: calc.: [525], found: [M+H]+ 526; 1H-NMR (250 MHz, DMSO-d6): δ [ppm]=10.20 (1H, s, COOH); 8.61 (1H, s, HCOOH); 8.09-6.77 (17H, m, 2 C(═NH)NH2, aryl-H); 5.37 (1H, m, N—CH—); 3.78 (3H, s, aryl-N—CH3); 3.33 (4H, s, aryl-CH2—CH2—); 2.98 (3H, s, CO—N—CH3).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Cl[C:10]1[C:11]2[N:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:12]=2[N:13]=[C:14]([NH:16]C(=O)C)[N:15]=1>C1COCC1>[Cl:24][C:22]1[CH:21]=[CH:20][C:12]2[N:13]=[C:14]([NH2:16])[N:15]=[C:10]([O:1][CH:2]3[CH2:6][CH2:5][O:4][CH2:3]3)[C:11]=2[N:23]=1
Reactant: O[C@@H]1CCOC1
Reactant: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(OC2CCOC2)c2nc(Cl)ccc2n1
Reaction time: 1 h
Yield: 51 %

Procedure:
(R)-(−)-3-hydroxy-tetrahydrofuran (0.62 mL) was added to a suspension of NaH (0.31 g, 7.7 mmol) in THF (15 mL). After stirring for 1 hour, the resulting mixture was added to a suspension of N-(4,6-dichloro-pyrido[3,2-d]pyrimidin-2-yl)-acetamide (0.9 g, 3.5 mmol) in THF (15 mL). The mixture was stirred at room temperature for 20 minutes, then diluted with EtOAC (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-(tetrahydro-furan-3-yloxy)-pyrido[3,2-d]pyrimidin-2-ylamine as a yellow solid (0.55 g, yield: 51%) which was characterized by its mass spectrum as follows: MS (m/z) 309.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[F:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][C:15]2[C:16](=[O:31])[NH:17][N:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1.N>>[Br:8][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:31])[C:15]([O:14][C:13]3[CH:32]=[CH:33][C:10]([F:9])=[CH:11][CH:12]=3)=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH:19]=[N:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Reactant: Brc1cccc(Br)c1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Br)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1,3-dibromobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 260 mg, 50.5%). mp 208–210° C. 1H NMR (300 MHz, CDCl3) δ 3.09 (s, 3H), 6.89–7.04 (m, 4H), 7.34 (t, J=9 Hz, 1H), 7.53 (br d, J=9 Hz, 1H), 7.64 (br d, J=9 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 7.87 (t, J=1.5 Hz, 1H), 8.08 (d, J=9 Hz, 2H), 8.09 (s, 1H). MS (DCI/NH3) m/z 517 (M+H)+, 534 (M+NH4)+. Anal. calc. for C23H16BrFN2O4S: C, 53.7; H, 3.11; N, 5.45. Found: C, 53.46; H, 2.88; N, 5.18.
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNCCOC.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([O:77]CC3C=CC=CC=3)=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH2:70][O:71][CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1>CO.ClCCl>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([OH:77])=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH2:70][O:71][CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1
Reactant: COCCN1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: COCCNCC[C@H](C)N
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COCCN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 60 %

Procedure:
In a manner similar to that described in example Z-35, from 16 (15 mg, 0.034 mmol) and [(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine bis hydrochloride, (19 mg, 0.087 mmol), (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo 7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid after silica gel chromatography (1-12% methanol/dichloromethane). This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a yellow solid (9 mg, 60%, 2 steps). 1H NMR (CDCl3) δ 12.56 (s, 1H), 10.51 (m, 1H), 8.29 (s, 1H) 7.32 (m, 2H), 6.98 (m, 2H), 5.03 (m, 1H), 4.65-4.59 (m, 2H), 4.53 (m, 1H), 4.2 (m, 1H), 3.61-3.40 (m, 2H), 3.34-3.13 (m, 3H), 3.08 (m, 1H), 2.94-2.84 (m, 2H), 2.68 (m, 1H), 2.07 (m, 1H), 1.50 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.14 (m, 1H); ES+ MS: 459 (M+1).