Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>ClCCl>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A vigorously stirring solution of N-phenyl-1,2-phenylenediamine (20.15 g) in dichloromethane (325 ml) and triethylamine (11.07 g) was cooled in an ice/acetone bath under nitrogen. p-Anisoyl chloride (18.66 g) dissolved in dichloromethane (100 ml) was added dropwise over a 20 minute period while maintaining a temperature of <5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for two hours. The organic solution was washed successively with water (200 ml), 2N aqueous HCl (80 ml), and saturated brine solution (160 ml), then dried over sodium sulfate and passed through a pad of silica (150 g). The silica was eluted with ethyl acetate (1 L) and the eluent was evaporated in vacuo to a pink solid. The solid was triturated overnight with ethyl ether (350 ml), cooled in an ice bath, filtered, and dried in vacuo to give the title compound as a light pink solid (21.67 g). 1H (300 MHz, CDCl3): d 3.82 (s, 3H), 5.75 (br s, 1H), 6.80-6.91(m, 5H), 7.12-7.29 (m, 5H), 7.62 (d, J=8.8 Hz, 2H), 8.15 (dd, J=1.7, 7.8 Hz, 1H), 8.36 (s, 1H); TLC (EtOAc/Hex, 1:4): Rf =0.24; m.p.: 148-150° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][CH:10]([SH:12])[CH3:11].C(O)CO.C(=O)([O-])[O-].[K+].[K+]>CC(O)C.[Cu]I>[CH:10]([S:12][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1)([CH3:11])[CH3:9]
Reactant: CC(C)S
Reactant: Oc1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)Sc1ccc(O)nc1
Reaction time: 0.75 h

Procedure:
5-iodopyridin-2-ol (1 g, 4.525 mmol), propane-2-thiol (689.3 mg, 840.6 μL, 9.050 mmol), ethylene glycol (842.9 mg, 757.3 μL, 13.58 mmol), CuI (172.4 mg, 0.9050 mmol) and potassium carbonate (1.877 g, 13.58 mmol) in IPA (7 mL) were heated under microwave conditions at 120° C. for 2 hours. The mixture was filtered through celite washing with DCM and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, loaded in DCM). The fractions were combined and concentrated in vacuo and the residue redissolved in EtOAc (10 mL) and stirred with 0.5 g of 3-Mercaptopropyl ethyl sulfide Silica for 45 minutes. The silica was removed by filtration and the solvent removed in vacuo to give the sub-title compound as a beige oil which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:11]([CH3:13])=[CH2:12])[CH:9]=[O:10].[CH2:14]([Mg]Cl)[CH:15]=[CH2:16]>>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH:9]([OH:10])[CH2:16][CH:15]=[CH2:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=CC[Mg]Cl
Reactant: C=C(C)C1(C=O)CCC(C)=CC1C
Product: C=CCC(O)C1(C(=C)C)CCC(C)=CC1C

Procedure:
In analogy to Example 3,1-(2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enyl)but-3-en-1-ol (91% yield) was prepared starting from 2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enecarbaldehyde and allylmagnesium chloride
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N+:4]([O-:19])[C:3]=1[C:9]#[N:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C)c(C#N)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)[n+]([O-])c1C#N
Temperature: 25 °C
Reaction time: 7 h
Yield: 57.4 %

Procedure:
To a solution of 3,6-dimethyl-2-pyridinecarbonitrile (8.20 g, may be prepared as described in Russell et al., J. Med. Chem., 48(5), 1367, (2005)) in chloroform (60 ml) was added dropwise a solution of m-chloroperbenzoic acid (20 g) in chloroform (210 ml) and the solution stirred at ambient temperature for 7 hours. Sodium sulphite (2.4 g) was added and the mixture stirred for 1.5 hours, filtered and the solid washed with dichloromethane. The filtrate was washed with saturated sodium bicarbonate (120 ml) and water (120 ml), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from ether to afford the title compound (5.28 g, 58%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:2]#[C:3][CH3:4].Cl.[CH:21]([O:24][NH2:25])([CH3:23])[CH3:22].Cl>N1C=CC=CC=1>[CH:21]([O:24][N:25]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])[N:11]=[CH:10][N:9]=1)([CH3:23])[CH3:22]
Reactant: CC#CCOc1cc(C(=O)c2ccccc2)ncn1
Reactant: CC(C)ON
Agent: Cl
Solvent: c1ccncc1
Product: CC#CCOc1cc(C(=NOC(C)C)c2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 3 ml of pyridine were added 0.3 g of 6-(2-butynyloxy)-4-benzoylpyrimidine and 0.20 g of O-isopropylhydroxylamine hydrochloride, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into 10% hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give two isomers of (6-(2-butynyloxy)-4-pyrimidyl)phenylketone O-isopropyloxime (referred to as isomers A and B).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C(=O)=O.CC(C)=O.C([Li])CCC.Cl>O1CCCC1>[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[CH:3][CH:4]=1)#[N:15]
Reactant: N#Cc1ccccc1-c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N#Cc1ccccc1-c1ccc(B(O)O)cc1
Temperature: -73 °C
Yield: 26 %

Procedure:
Add 2-(4-bromophenyl)benzenecarbonitrile (1.29 g, 0.005 moles, preparation 61), tetrahydrofuran (52 mL), and triisopropyl borate (2.82 grams, 0.015 moles) to a 100 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, dry ice-acetone bath, and addition funnel. Stir the mixture under nitrogen and cool the contents of the 100 mL 3-neck round-bottom flask to −73° C. Transfer a solution of n-butyl lithium 1.6 M in hexanes (8.7 mL, 0.0139 moles) via cannula to the addition funnel. Add n-butyl lithium (4.7 mL, 0.0075 moles) to the reaction mixture over 7 minutes while maintaining −65 to −73° C. Slowly warm the reaction mixture to −15° C. Cool the reaction mixture to −70° C. Add n-butyl lithium (3.0 mL, 0.0048 moles) to the reaction mixture dropwise. Slowly warm the reaction mixture to −15° C. Cool the reaction mixture to −60° C. Add n-butyl lithium (1.0 mL, 0.0016 moles) to the reaction mixture dropwise. Slowly warm the reaction mixture to −15° C. Cool the reaction mixture to −30° C. Add 1.0 N hydrochloric acid (20 mL, 0.02 moles). Remove the dry ice-acetone bath, and allow the reaction mixture to warm to 23° C. Transfer the reaction m mixture to a separatory funnel. Separate the phases and concentrate the organic phase to a solid under reduced pressure (15-25 mm). Add water (50 mL), 5N NaOH until pH 11.5 is observed, dichloromethane (40 mL), and tetrahydrofuran (20 mL). Transfer the reaction mixture to a separatory funnel and separate the phases. Acidify the aqueous phase and concentrate the suspension under reduced pressure (15-25 mm) to remove residual organic solvents. Collect the precipitate by filtration. Vacuum (15-25 mm) dry the filter cake at 45° C. to provide the title compound (0.30 g, 0.0013 moles) in 26.9% yield. 1H NMR (DMSO-d6, 500.0 MHz): δ 8.21 (s, 2H); 7.98 (dd, 1H, J=1.5, 8); 7.95 (d, 2H, J=8); 7.82 (dt, 1H, J=1.5, 7.5); 7.66 (d, 1H, J=7); 7.61 (dt, 1H, J=1, 8); 7.57 (d, 2H, J=8).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH2:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:41][C@@H:42]1[C@H:46]([CH:47]=O)[CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43]1>C(Cl)Cl>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH:26][CH2:47][C@H:46]1[C@@H:42]([F:41])[CH2:43][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:45]1)[C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Reactant: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of (R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropan-1-amine (140 mg, 0.378 mmol) in CH2Cl2 (7.0 mL) was added NaBH(OAc)3 (400 mg, 1.89 mmol). To this solution, the crude (3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylate (obtained from 2.0 equiv. of (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate) in CH2Cl2 (1.0 mL) was added over 3 minute at room temperature. After stirred for 20 min, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified on preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (138 mg, 60%). LC/MS (uplc) MH+ 608.3, 1.14 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>ClCCl>[O:8]=[C:6]1[CH:7]([C:21](=[O:24])[CH2:22][CH3:23])[C:2](=[O:1])[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1
Reactant: CCOC(=O)C1CC(=O)CC(=O)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(=O)C(C(=O)CC)C(=O)C1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
4.2 g of ethyl 3,5-dioxocyclohexanecarboxylate and 3.4 g of triethylamine were dissolved in 50 ml of dichloromethane, to which was added dropwise 2.9 g of propionyl chloride under stirring at room temperature. The resultant mixture was allowed to react at ambient temperature for 2 hours, after which the reaction solution was washed with water and admixed with a dilute aqueous sodium bicarbonate solution to remove the acidic matters from the reaction solution. The organic layer was then separated from the aqueous phase, dried and concentrated to a small volume. The concentrated solution was taken up in 20 ml of toluene, followed by addition of 0.5 g of 4-N,N-dimethylaminopyridine and heating the mixture at 85° C. for 3 hours. Thereafter, the toluene was removed from the reaction solution by distillation under reduced pressure, and the residue was chromatographed on silica gel using benzene as developing solvent to afford 2.5 g of the title compound (Compound No. 9 of Table 1) as colorless flakes having a melting point of 55°- 56° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16](OC3C=CC([N+]([O-])=O)=CC=3)=[O:17])[CH2:13][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:16]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][C:2]([F:32])([F:33])[F:1])=[CH:9][CH:8]=3)[CH2:11][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]2)=[O:17])[CH2:37][CH2:36]1
Reactant: OC1CCNCC1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 150 °C

Procedure:
1.20 g (2.57 mmol) of the compound from Example 54A, 781 mg (7.72 mmol) of 4-hydroxypiperidine and 533 mg (3.86 mmol) of potassium carbonate were added to 14 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 45 min. For workup, the reaction solutions were combined and filtered, and the residue was purified by means of preparative HPLC. Yield: 733 mg (66% of theory)
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:2]2[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=23)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: NCCCN1CCOCC1
Product: Cc1nnc(NCCCN2CCOCC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-(3-aminopropyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 295°-296° C. (after recrystallization from ethanol).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(#N)C>[C:8]1([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: CC#N
Product: c1ccc(-c2ccc(N3CCNCC3)nn2)cc1
Yield: 99 %

Procedure:
To a solution of 3-chloro-6-phenylpyridazine (0.960 g, 5.000 mmol) in acetonitrile (25 mL) was added piperazine (2.580 g, 30.00 mmol) and the mixture was stirred at reflux for 16 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over MgSO4 and concentrated. The title compound was obtained in 99% yield (1.200 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH2:4][CH2:3]1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCC(=O)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
Compound 447 (150 mg, 0.517 mmol) was dissolved in DMF (2.5 mL), and isonicotinic acid (191 mg, 1.55 mmol), EDC hydrochloride (298 mg, 1.55 mmol) and 1-hydroxybenzotriazole monohydrate (237 mg, 1.55 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 448 (115 mg, 66%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](C1C=CC(O)=C(C=1)C(OCC)=O)=O>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CCOC(=O)c1cc(C=O)ccc1O
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CO
Product: COC(=O)c1cc(O)ccc1O
Yield: 94 %

Procedure:
2,5-Dihydroxybenzoic acid was converted to its methyl ester using catalytic sulfuric acid in methanol following the same protocol as for esterification 2c in 94% yield. mp 86.4°-88.5° C. IR(KBr): cm-1 3346, 1684.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:13])([O:11][CH3:12])[CH3:10])[CH2:3][CH:4]=O.[CH3:14][O:15][C:16](=[O:29])/[C:17](/[CH3:28])=[C:18](\P(OCC)(OCC)=O)/[CH3:19].[Na]>C1C=CC=CC=1.CO>[CH3:14][O:15][C:16](=[O:29])[C:17]([CH3:28])=[CH:18][CH:19]=[CH:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])([CH3:13])[CH3:10]
Reactant: COC(C)(C)CCCC(C)CC=O
Reactant: CCOP(=O)(OCC)/C(C)=C(/C)C(=O)OC
Agent: [Na]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C)=CC=CCC(C)CCCC(C)(C)OC
Temperature: 60 °C
Reaction time: 5 h

Procedure:
29.5 g of 3,7-dimethyl-7-methoxy-octanal and 42 g of diethylphosphono-α-methyl-crotonic acid methyl ester are dissolved in 100 ml of absolute benzene. To this solution there is added dropwise 4.1 g of sodium dissolved in 50 ml of absolute methanol. The mixture is stirred for 5 hours at 60°C., poured on to ice-water and extracted with diethyl ether. The ethereal solution is washed with water, then with aqueous sodium bicarbonate solution and once again with water, dried with sodium sulphate, filtered and concentrated on a rotary evaporator. After chromatography on a 30-fold amount of Kieselgel, using hexane/diethyl ether (9:1 parts by volume) as the eluant, there is obtained 11-methoxy-2,7,11-trimethyl-2,4-dodecadienoic acid methyl ester; boiling point 100°C/0.002 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:18][CH2:19][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCCI
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc2oc(C(=O)OCC)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with iodopropane (0.5 mL), K2CO3 (200 mg) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent gave the crude product, which was purified by column chromatography to give 176 mg of 3-methyl-4-propoxy-benzofuran-2-carboxylic acid ethyl ester as white solid.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:34]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[I:34][C:23]1[C:22]([C:25]2[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=2)=[N:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:24]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(-c2ccn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)s1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2I)s1
Temperature: 80 °C
Reaction time: 24 h
Yield: 95.7 %

Procedure:
20 g methyl 5-(1-trityl-1H-3-pyrazolyl)-2-thiophene carboxylate and 10.6 g N-iodosuccinimide were stirred in 200 mL N,N-dimethylformamide at 80° C. for 24 hours. Additional N-iodosuccinimide, 10.6 g, was added thereto and stirred at 80° C. for 24 hours, and then an aqueous solution of sodium thiosulfate and an aqueous solution of sodium bicarbonate were added thereto and stirred for 1 hour, and the formed solid was collected by filtration. The solid was dissolved in dichloromethane and dried over magnesium sulfate, and the solvent was removed, whereby 24.5 g of the title compound was obtained as colorless crystals.
Reaction SMILES: CO[C:3](=[S:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>CCOCC>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16])=[S:11])=[CH:9][CH:8]=1
Reactant: COC(=S)c1ccc(Cl)cc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)C[C@H](NC(=S)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.6 %

Procedure:
A mixture of methyl-4-chlorothiobenzoate (2.11 g, 11.3 mmol), aspartic acid (2.7 g, 2.02 mmol), aq NaOH (3N, 8.8 ml), and Et2O (8 ml) were vigourously stirred at room temperature for 3 days. The aq. layer was separated, acidified (dil.HCl), and extracted with Et2O (2×25 ml). The combined ether extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to yield N-p-chlorothiobenzoylaspartic acid (0.23 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.[C:23]1(C)C=CC(NN)=CC=1>CCO.O>[C:4]1([CH3:23])[CH:3]=[CH:2][C:1]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]3)=[N:8]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(NN)cc1
Reactant: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (500 mg, 2.8 mmol) (from Example 137A Step 2) in EtOH (10 mL) was added water (7.2 mL) and 1 M NaOH (2.8 mL) followed by p-tolylhydrazine hydrochloride (444 mg, 2.8 mmol) and the solution heated at 80° C. overnight. The solution was cooled to rt, diluted with water and extracted with 2 portions of EtOAc. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude solid was purified using silica gel chromatography using a gradient of 5-25% EtOAc/hexane to give 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (452 mg, 57% yield). LC-MS (ESI) m/z 282 (M+H)+
Reaction SMILES: Cl[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:28]=[C:29]([O:31][CH:32]([CH3:34])[CH3:33])[CH:30]=1)[C:19]([NH:21][C:22]1[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=1)=[O:20].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:34][CH:32]([O:31][C:29]1[CH:28]=[C:18]([CH:17]=[C:16]([O:15][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:14])[N:8]([CH3:13])[CH2:9][CH2:10][O:11][C:12]=3[CH:2]=2)[CH:30]=1)[C:19]([NH:21][C:22]1[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=1)=[O:20])[CH3:33]
Reactant: CC(C)Oc1cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 140 °C

Procedure:
To a solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (160 mg, 0.32 mmol) in ethanol (3 mL) was added ammonium formate (208 mg, 10 equivs) in one portion. The reaction was blanketed with argon and 10% Palladium on carbon (40 mg) was added. The mixture was heated to 140° C. for 10 minutes in a Smith Creator microwave. The reaction mixture was filtered through diatomaceous earth and the filter pad was washed well with ethyl acetate. The filtrate was concentrated in vacuo and the residue purified by chromatography on alumina, eluting with 50-100% ethyl acetate in hexanes, to afford the title compound as a colourless oil which foamed under high vacuum (65 mg).