Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:36]=[CH:35]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:37]6[N:36]=[CH:35][N:34]([CH3:33])[CH:38]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1cnc(C2(N)CC2)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cn(C)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.07 g, 1.1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml, 3 eq) were dissolved in dichloromethane and the above solution was stirred at room temperature for 18 h. Later water was added and organic layer was separated. The organic layer was washed with water and the crude product was purified by Prep. HPLC. Yield: 24.69 mg (10%) 1HNMR (400 MHz, CDCl3): δ 1.39 (s, 4H), 2.30 (s, 3H), 2.99-3.01 (d, J=4.6 Hz, 3H), 3.81 (s, 3H), 4.04 (s, 3H), 5.90 (s, 1H), 6.87 (s, 1H), 7.16-7.25 (m, 3H), 7.24 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.98-7.99 (m, 3H), 8.29 (s, 1H), 8.95 (s, 1H). LCMS: (ES+) m/z=553.2 (M+H). Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH Flow: 1 ML/Min
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:20]([CH3:22])[CH3:21])[C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5].[C:23]([O:27][C:28]([N:30]([CH3:36])[C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:23]([O:27][C:28]([N:30]([CH3:36])[C@@H:31]([CH3:35])[C:32]([NH:2][C@@H:3]([CH:20]([CH3:21])[CH3:22])[C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of (S)-ethyl 1-((S)-2-amino-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride (1.6 g, 4.88 mmol, Eq: 1.00) in DMF (20 mL) was added (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.2 g, 5.9 mmol, Eq: 1.21) and HATU (2.2 g, 5.79 mmol, Eq: 1.19). Diisopropylethylamine (2.2 mL, 12.6 mmol, Eq: 2.58) was then added and the resulting yellow solution was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and hexanes (50 mL) and washed with 0.1 M aqueous KHSO4, 0.1 M aqueous NaOH, and brine and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% EtOAc/DCM:hexanes 1:1) then 20% to 40% EtOAc/DCM:hexanes 1:1) after first spot has eluted) to give (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (eluted second 1.9 g), m/z=477 (M+H).
Reaction SMILES: [NH2:1][S:2]([CH:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])(=[O:4])=[O:3].Cl>C(O)C.[Pd]>[NH2:1][S:2]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])(=[O:3])=[O:4]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(N)(=O)=O)cc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(N)(=O)=O)cc12
Yield: 49.8 %

Procedure:
(R)-5-(2-Aminosulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (157 mg, 0.5 mmol) was dissolved in absolute ethanol (10 mL) and added to a solution of ethanolic hydrogen chloride (25 ml) (prepared from acetyl chloride (38 μL, 0.53 mmol) and absolute ethanol (25 mL)). 10% palladium-on-carbon (125 mg) was added. This solution was hydrogenated under a hydrogen atmosphere (15 p.s.i.) at room temperature for 18 hours. The resultant reaction mixture was filtered through diatomaceous earth (Celite trademark or Arbacell-trademark)) washed with absolute ethanol and the combined filtrates evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient solvent mixture up to CH2Cl2 : MeOH:NH4OH 93:7:1 to give the title compound as a colourless oil (80 mg, 51%). Anal. Calcd for C16H23N3O2S. l/4 MeOH. 1/3 H2O: C, 58.21; H, 7.36; N, 12.54. Found: C, 58.60; H, 7.40; N, 12.57 [α]25D =+69° (c=0 1, MeOH)
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH3:47])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:44]([O:43][CH:39]([O:40][CH2:41][CH3:42])[C@@H:38]([N:26]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH3:47])[CH3:46])[CH3:45]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 120 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=[O:9])[CH3:8])[CH3:2].Cl.[CH3:13][O:14][NH2:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[C:5](=[N:15][O:14][CH3:13])[CH2:6][C:7](=[O:9])[CH3:8])[CH3:2]
Reactant: CON
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(C)=O)=NOC
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.1 %

Procedure:
A mixture of 2,4-dioxo-pentanoic acid ethyl ester (5.4 mL, 50 mmol), methoxyamine hydrochloride (4.4 g, 52.5 mmol), molecular sieves (3 Å, 35 g) and sodium sulfate (15 g) in ethanol (50 mL) is stirred at ambient temperature for 5 hours. The reaction mixture is filtered and washed with ethanol. The combined filtrate is concentrated under reduced pressure and is partitioned between ethyl ether and saturated sodium bicarbonate. The organic layer is dried (MgSO4), filtered, and concentrated. The residue is purified by column chromatography (0 to 15% EtOAc in hexanes) to give the title compound as a colorless oil (3 g, 32%). 1H NMR (400 MHz, CDCl3) δ 4.33 (q, 2H), 4.06 (s, 3H), 3.70 (s, 3H), 2.20 (s, 3H), 1.34 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: CN1CCN(CCO)CC1
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN1CCN(CCn2nc(-c3cccc(F)c3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
A mixture of 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-(4-methylpiperazin-1-yl)ethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 8.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:61][C:62]([F:81])([F:80])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:70]2[C:71]3[CH2:79][CH2:78][NH:77][CH2:76][C:72]=3[N:73]=[CH:74][N:75]=2)=[CH:65][CH:64]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:51]1([CH3:54])[CH:52]=[CH:53][C:48]([N:77]2[CH2:78][CH2:79][C:71]3[C:70]([NH:69][C:66]4[CH:65]=[CH:64][C:63]([C:62]([F:81])([F:61])[F:80])=[CH:68][CH:67]=4)=[N:75][CH:74]=[N:73][C:72]=3[CH2:76]2)=[CH:49][CH:50]=1
Reactant: Cc1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(N2CCc3c(ncnc3Nc3ccc(C(F)(F)F)cc3)C2)cc1
Temperature: 160 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
To 2 mL of dioxane was added 10 mol % of palladium(II)acetate (12 mg) and 20 mol % rac-BINAP (58 mg). After stirring for 3 hours, 4-bromotoluene (90 mg, 0.53 mmol), cesium carbonate (682 mg, 2.12 mmol), N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.51 mmol) and activated molecular sieves (340 mg) were added. The mixture was sonicated for 10 minutes and heated in a sealed tube via microwave at 160° C. for 3 hours in a Personal Chemistry Microwave (Smith Creator). After completion, the mixture was filtered through celite, evaporated and purified by flash chromatography over silica gel using a 0-100% gradient of ethyl acetate/hexanes to give the desired product as a white solid (34 mg).
Reaction SMILES: [OH-].[Li+].C([N:6]([CH2:15][C@H:16]1[C@H:20]([OH:21])[CH2:19][C@@H:18]([Cl:22])[C@@H:17]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)(=O)C>C1COCC1>[Cl:22][C@H:18]1[C@H:17]([CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@@H:16]([CH2:15][NH:6][C:7]2[CH:8]=[C:9]([Cl:14])[CH:10]=[C:11]([Cl:13])[CH:12]=2)[C@H:20]([OH:21])[CH2:19]1
Reactant: CC(=O)N(C[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1O)c1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CNc2cc(Cl)cc(Cl)c2)[C@H](O)C[C@H]1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
Lithium hydroxide (21 μL of a 1.0 M aqueous solution, 0.021 mmol) was added to a solution of acetate 10 (2 mg, 0.004 mmol) in THF (0.2 mL). After stirring 3 d at room temperature, the reaction mixture was partitioned between aqueous HCl (1.0 N, 2 mL) and EtOAc (2 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford 1 mg (55%) of the title compound (11).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CO[C:11](OC)([N:13]([CH3:15])[CH3:14])[CH3:12].COC1CCCC1>>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[C:11](/[N:13]([CH3:15])[CH3:14])\[CH3:12])=[CH:4][CH:3]=1
Reactant: COC(C)(OC)N(C)C
Reactant: Nc1ccc(Cl)nn1
Solvent: COC1CCCC1
Product: C/C(=N\c1ccc(Cl)nn1)N(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 6-chloropyridazin-3-amine (1.500 kg, 11.58 mol); 1,1-dimethoxy-N,N-dimethylethanamine (2.313 kg, 17.37 mol) and cyclopentyl methyl ether (8.25 L) then heat to 98° C. while distilling off the resulting methanol byproduct. After 4 h, the reaction mixture is cooled to ambient temperature and heptanes (11.2 L) is added to the reaction solution for crystallizing the product. The title compound is collected by filtration and is dried. (1.494 kg, 64.95%; mp=73° C.)
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[O:10]=[C:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl-].[NH4+]>C1COCC1>[OH:10][C:11]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1ccccc1[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
60 ml (60 mmol) of 1M ortho-tolylmagnesium chloride in THF are added dropwise to a solution of 7.4 g (43 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate in 60 ml of tetrahydrofuran cooled to −78° C. After stirring for 1 h at ambient temperature, the mixture is hydrolysed with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated. The beige solid obtained is purified by silica gel chromatography, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 8.9 g of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of a white solid with a yield of 79%.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[CH2:33]([O:32][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[CH:8][CH:7]=1)[C:3]([OH:35])=[O:2])[CH3:34]
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)Cc1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A solution of 2-ethoxy-3-{4-[2-(heptyl-p-tolylacetyl-amino)-ethyl]-phenyl}-propionic acid methyl ester (21 mg, 0.044 mmol) and 1 M LiOH (0.131 mmol, 0.131 mL) in tetrahydrofuran (1 mL) was allowed to stir at room temperature for 24 hours. 2 N HCL was then added until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 2-ethoxy-3-{4-[2-(heptyl-p-tolylacetyl-amino)-ethyl]-phenyl}-propionic acid as a clear oil (19.5 mg, 95%).
Reaction SMILES: [AlH4-].[Li+].[NH2:3][C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[C:13]([N:15]([CH3:17])[CH3:16])=O>C1COCC1>[CH3:17][N:15]([CH2:13][C@@H:5]1[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:4]1[NH2:3])[CH3:16]
Reactant: CN(C)C(=O)[C@@H]1Cc2ccccc2[C@@H]1N
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1Cc2ccccc2[C@@H]1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a stirred suspension of lithium tetrahydroaluminate (256 mg, 6.74 mmol) in THF (20.0 mL) was added a solution of rel-(1R,2R)-1-amino-N,N-dimethylindane-2-carboxamide (580 mg, 2.70 mmol) in THF (10.0 mL) at 0° C. under an atmosphere of Argon, and then the mixture was stirred for 1 h at 60° C. following by stirring for 14 h at 23° C. The reaction mixture was quenched by addition of water and 1.00 M NaOH (5.00 mL), and the resulting mixture was stirred for 2 h. This suspension was filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (5 to 20% Methanol/DCM with 1% NH4OH) to afford the title compound (438 mg, 95%) as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][CH:9]=2)[NH:4][N:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][CH:20](Cl)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:16][CH:17]1[CH2:22][CH2:21][CH:20]([N:4]2[C:5]3=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][CH:9]=[C:10]3[C:2]([Br:1])=[N:3]2)[CH2:19][CH2:18]1
Reactant: CCCCNc1ncc2c(Br)n[nH]c2n1
Reactant: OC1CCC(Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1ncc2c(Br)nn(C3CCC(O)CC3)c2n1
Temperature: 150 °C

Procedure:
To a solution of 3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (122 mg, 0.45 mmol) and 4-hydroxy-cyclohexyl chloride (260 mg, 1.9 mmol) in DMF (6.0 mL) was added K2CO3 (270 g, 2.0 mmol). The mixture was heated at 150° C. for overnight. After the reaction was cooled to room temperature, the reaction was quenched with H2O. The reaction mixture was partitioned in H2O and EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic phase were dried (Na2SO4) and concentrated. The residue was purified by Isco to provide a mixture of cis- and trans-1-(4-hydroxy-cyclohexyl)-3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (90 mg, 54%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.BrC1C=CC(C(Cl)=O)=CC=1.BrCC1C=CC(SC)=C(F)C=1>>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:6])=[CH:14][CH:13]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: CSc1ccc(CBr)cc1F
Agent: O=C(Cl)c1ccc(Br)cc1
Product: O=C(Cc1ccc(Br)cc1)c1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure of Example 169 step 3 using 3-fluorobenzoyl chloride and 4-bromobenzylbromide, instead of 4-bromobenzoyl chloride and 4-(bromomethyl)-2-fluoro-1-(methylsulfanyl)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([CH:6]=[O:7])=[C:4]([Cl:11])[CH:3]=1.[CH3:12][Mg]Br.BrC1C=C(C(O)C)C=C(F)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([CH:6]([OH:7])[CH3:12])=[C:8]([Cl:10])[CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1c(Cl)cc(Br)cc1Cl
Agent: CC(O)c1cc(F)cc(Br)c1
Product: CC(O)c1c(Cl)cc(Br)cc1Cl

Procedure:
The title compound was prepared from 4-bromo-2,6-dichlorobenzaldehyde (prepared according to WO 2008/021851) by reaction with methylmagnesium bromide following the procedure for 1-(3-bromo-5-fluorophenyl)ethanol as described.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=2)[N:18]=1)=[O:7].[OH-].[Na+].CO.Cl>O>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=2)[N:18]=1)=[O:7]
Reactant: CCOC(=O)c1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1cccc(Oc2ccc3nc(C(=O)O)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
A mixture of ethyl 6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylate (470 mg, 1.00 mmol), 8N aqueous sodium hydroxide solution (2.0 mL) and methanol (6.0 mL) was stirred at room temperature for 4 hr. 6N Hydrochloric acid (2.7 mL) and water (25 mL) were added to the mixture, and the mixture was extracted with ethyl acetate (50 mL). The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (425 mg, 96%) as a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:11][CH3:12])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][Cl:14])=[CH:19][CH:20]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc2ocnc2c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2ocnc2c1
Yield: 16 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(benzo[d]oxazol-5-yl)propan-1-one (0.6 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.42 g, 1.5 eq) to give 0.23 g desired product (15%, Z/E=1/1) as a white solid.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].C1COCC1.[Br:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O1CCOS1(=O)=O.Cl>CN(C=O)C.C(OCC)(=O)C>[Br:12][C:13]1[CH:17]=[CH:16][N:15]([CH2:1][CH2:2][OH:4])[N:14]=1
Reactant: Brc1cc[nH]n1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: O=S1(=O)OCCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCn1ccc(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide in THF (0.510 mL, 0.510 mmol) was added to a solution of 3-bromo-1H-pyrazole (50.0 mg, 0.340 mmol) in DMF (3 mL) and stirred at r.t. for 10 min, and then 1,3,2-dioxathiolane 2,2-dioxide (0.0633 g, 0.510 mmol) was added and the stirred at r.t. for 1 h. At this time, conc. HCl (0.3 mL) was added to the above reaction mixture and then stirred at r.t. overnight. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered, and concentrated to give the crude product which was directly used in the next reaction without further purification. LCMS (M+H)+: m/z=191.0.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.Cl[CH2:16][CH2:17][S:18][CH2:19][CH2:20]Cl.CC(CC)=O.CC(C)=O>C(OCC)(=O)C>[NH:10]=[C:8]1[N:7]([CH2:16][CH2:17][S:18][CH2:19][CH3:20])[C:6]2[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][C:5]=2[S:9]1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: ClCCSCCCl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: CCSCCn1c(=N)sc2cc(C(F)(F)F)ccc21
Temperature: 20 °C

Procedure:
2-Imino-3(2-ethylthioethyl)-6-trifluoromethylbenzothiazoline can be obtained in the following manner: A mixture of 6-trifluoromethyl-2-benzothiazolamine (32.3 g), 2-chloroethylsulphide (18 cc) and methylethylketone (20 cc) is heated under reflux for 16 hours. After cooling to 20° C., acetone (20 cc) is added and the solution obtained is poured into a mixture of ethyl acetate (200 cc) and petroleum ether (40°-60° C., 200 cc). The precipitate obtained is filtered off, taken up in water, and made alkaline with 28% ammonia. The base is then extracted with a mixture of ethylacetate (150 cc) and cyclohexane (150 cc) and purified on a column of silica (600 g), eluting with a mixture of ethylacetate and cyclohexane (50:50 by volume). 2-Imino-3-(2-ethylthioethyl)-6-trifluoromethylbenzothiazoline (33.2 g), m.p. 50° C., is thus obtained.