Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:5]2[N:6]=[CH:7][C:8]([NH2:11])=[C:9]([NH2:10])[N:4]2[N:3]=1.[C:13]1([CH2:19][C:20](=[O:25])C(OC)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)=O>[CH3:1][C:2]1[CH:12]=[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[N:10][C:20]([OH:25])=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[N:4]2[N:3]=1
Reactant: COC(=O)C(=O)Cc1ccccc1
Reactant: Cc1cc2ncc(N)c(N)n2n1
Solvent: CC(=O)O
Product: Cc1cc2ncc3nc(-c4ccccc4)c(O)nc3n2n1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A 40-mL scintillation vial containing Compound (10-3) (320 mg, 2.0 mmol, 1 eq.), methyl phenylpyruvate (360 mg, 2.2 mmol, 1.1 eq.), and 20% AcOH (20 mL) was stirred at room temperature for 1.5 hours and at 65° C. for 4 hours. The mixture was allowed to cool and the precipitated solid was filtered and washed successively with water (15 mL) and Et2O (2×10 mL). The solid was dried in vacuo to give Compound (10-4) as a yellowish solid.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH2:24][Cl:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[Cl:25][CH2:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: NNc1nc2ccc(OCCl)cc2s1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: O=C(NNc1nc2ccc(OCCl)cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4g was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and 2-hydrazino-6-chloromethoxybenzothiazole (298 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 237 mg, 70%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1)[C:22](O)=[O:23].O1C2(CCN(C#N)CC2)OCC1.FC(F)(F)C(O)=O>ClCCl>[CH:15]1([N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[C:19]([F:18])[CH:20]=2)[CH2:16][CH2:17]1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Agent: N#CN1CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1

Procedure:
The title compound is prepared from 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Intermediate 1. The cleavage of the BOC group is accomplished by using trifluoroacetic acid in dichloromethane. LC (method 14): tR=0.98 min; Mass spectrum (ESI+): m/z=330 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH3:13])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:18]([O:23][CH2:24][CH3:25])(=[O:22])[CH:19]([CH3:21])O.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH3:13])[C:3]=1[C:4]([O:6][CH2:21][CH2:19][C:18]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(C)O
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCOC(=O)c1c(Cl)ccc(Cl)c1OC

Procedure:
To a 100-milliliter round bottom flask provided with a reflux condenser was charged 20 grams of 2,5-dichloro-6-methoxybenzoic acid (prepared as described in paragraph (a) of this Example) and 30 milliliters (48 grams) of thionyl chloride. The mixture was heated to reflux and maintained at reflux for two hours after which the miture was stripped under vacuum to remove excess thionyl chloride. The oily residue was poured into a separatory funnel along with water and benzene and the contents thoroughly mixed. A small amount of potassium chloride was added to assist phase separation and the benzene layer was washed several times with water. Benzene was then stripped under vacuum and the residue was vacuum distilled. 20.8 grams of a clear oil ws collected, the oil having a boiling point of 82°-84° C. at 0.1 mm Hg. 12 grams of this oil and 75 milliliters of benzene were charged to a 250-milliter round bottom flask provided with a reflux condenser. To this stirred mixture was added, dropwise, 6 milliliters of ethyl lactate and 6 grams of triethylamine in 40 milliliters of benzene. (Some solids formation was noted.) The mixture was then heated to reflux and maintained at reflux for 31/2 hours after which the mixture was cooled and filtered, 1.7 grams of amine hydrochloride solids being collected. 5 milliliters of pyridine was added to the filtrate and the mixture was heated to reflux and maintained at reflux overnight. The mixture was then filtered (3.2 grams of amine hydrochloride solids being collected) and the filtrate was washed consecutively with dilute hydrochloric acid, water, dilute aqueous sodium hydroxide and twice more with water. Benzene was then stripped under vacuum leaving a black oil. The oil was vacuum distilled and 6.7 grams of clear oil was collected at 142°-144° C. and 0.2 mm Hg., which oil was identified by NMR spectroscopy as 2,5-dichloro-6-methoxy-benzoic acid, (ethoxycarbonyl)ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C4CCCCO4)[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-3-[1-(6-Fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (Stage 279.1, 250 mg, 0.511 mmol) was dissolved in DCM (5 mL). HCl in dioxane (4 N, 0.5 mL) was added and the RM was stirred 1 h at rt. It was then diluted with EtOAc and washed with a saturated NaHCO3 sol. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to afford the title compound as a white solid (tR 0.98 min (conditions 2), MH+=406, 1H-NMR in DMSO-d6: 8.39 (s, 1H); 8.07 (d, 2H); 8.01 (d, 1H); 7.69 (s, 1H); 7.61 (s, 1H); 7.51 (d, 1H); 7.47 (d, 1H); 7.23 (d, 1H); 4.95 (t, 1H); 4.76 (q, 1H); 4.18 (t, 2H); 3.78 (s, 3H); 3.75 (q, 2H); 1.79 (d, 3H)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:13]1([C:18]2[N:23]=[C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH2:29][CH2:30][NH2:31])[CH:21]=[C:20]([CH3:32])[N:19]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:31][CH2:30][CH2:29][N:25]3[CH2:26][CH2:27][CH2:28][CH:24]3[C:22]3[CH:21]=[C:20]([CH3:32])[N:19]=[C:18]([N:13]4[CH:17]=[CH:16][N:15]=[CH:14]4)[N:23]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CCc1ccc2c(c1)OCO2
Reactant: Cc1cc(C2CCCN2CCN)nc(-n2ccnc2)n1
Product: Cc1cc(C2CCCN2CCNCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1

Procedure:
(2-Benzo[1,3]dioxol-5-yl-ethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine was prepared following the procedures described in the preparation of Example 127 using benzo[1,3]dioxol-5-yl-acetaldehyde and 2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethylamine. [M+H]+ 421.55; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.86 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.90 (d, 1H), 6.65 (d, 1H), 6.60 (dd, 1H), 5.88 (s, 2H), 3.50 (t, 1H), 3.21 (m, 1H), 2.82-2.64 (m, 5H), 2.50 (s, 3H), 2.40-2.20 (m, 4H), 1.95-1.66 (m, 4H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Ca+2].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][C:18]4[CH:19]=[CH:20][C:21]([C:24]5[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=5)=[CH:22][N:23]=4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COc1cc(OC)nc(-c2ccc(Cl)nc2)n1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)n1

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (125 mg, 0.58 mmol), 2-(6-chloro-pyridin-3-yl)-4,6-dimethoxy-pyrimidine (145 mg, 0.58 mmol), calcium carbonate (720 mg, 2.2 mmol) and dimethylformamide (4 ml) were heated in a microwave reactor at 180° C. for 900 seconds at 300 W. The mixture was diluted with ethyl acetate, washed with water, then brine and dried over sodium sulphate. The residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title product. MS (ES+) m/e 433 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][CH:9]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[OH:8][CH:9]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccccc1
Reactant: CCCCCC(O)c1cccc(CBr)c1
Product: CCCCCC(O)c1cccc(CNc2ccccc2)c1

Procedure:
For compounds in which X is --NR2 --(CHR1)n --, the corresponding amino starting compounds are employed to form the desired amino compound. Thus, aniline is condensed with 3-(1-hydroxyhexyl)benzylbromide to form 2-[3-(1-hydroxyhexyl)benzylamino]benzene. Alternatively, benzyl bromide is condensed with 3-(1-hydroxyhexyl)aniline to form 2-[3-(1-hydroxyhexyl)anilinomethyl]benzene.
Reaction SMILES: O[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[CH:5]=[CH:4]C=1.ClN(C(C)C)C(C)C.C(NC(C)C)(C)C.Cl[O-:30].[Na+].[CH:32]([Cl:35])(Cl)Cl>>[Cl:35][C:32]1[C:4]([OH:30])=[CH:5][C:6]2[C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[O:9][C:10]=2[CH:2]=1
Reactant: CC1(C)Oc2c(O)cccc2C1=O
Reactant: [O-]Cl
Reactant: ClC(Cl)Cl
Agent: CC(C)N(Cl)C(C)C
Agent: [Na+]
Solvent: CC(C)NC(C)C
Product: CC1(C)Oc2cc(Cl)c(O)cc2C1=O
Reaction time: 10 h

Procedure:
25 mmol 7-Hydroxy-2,2-dimethyl-benzofuran-3-one and 30 g silica gel are stirred in 200 ml chloroform. A solution of 25 mmol N-chloro-diisopropylamine in 100 ml chloroform (prepared from diisopropylamine and aqueous sodium hypochlorite solution, extracted in chloroform, concentration determined iodometrically) is added dropwise. After stirring for 10 hours it is filtered and the filtrate is shaken out with water. The solution is dried over sodium sulfate. The solvent is removed by distillation at 300 mbar. The residue is separated by column chromatography (silica gel: ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.O.Cl>C(O)C.[Fe]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)cnc1N
Yield: 102.6 %

Procedure:
To a solution of 2-amino-5-fluoro-3-nitropyridine (0.42 g, 2.3 mmol) and iron powder (1.6 g, 28 mmol) in ethanol (10 ml) were added water (0.5 ml, 28 mmol) and hydrochloric acid (27 μl, 0.32 mmol). The mixture was refluxed for 1 h. An additional amount of iron powder (0.2 g, 3.6 mmol) was added and the mixture was refluxed for 30 min. The reaction mixture was filtered through celite and evaporation under reduced pressure of the solvent gave 0.3 g (100%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([C@@H:24]([OH:26])[CH3:25])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:29](O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:29]([O:26][C@@H:24]([C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:27])([F:1])[F:28])[CH:5]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1)[CH3:25])(=[O:31])[CH3:30]
Reactant: C[C@H](O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reactant: CC(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of (1S)-1-[5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-yl]ethanol (390 mg, 1.00 mmol), acetic acid (0.114 mL, 2.00 mmol) and triphenylphosphine (394 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise 40% diethyl azodicarboxylate-toluene solution (0.653 mL, 1.50 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) to give the title compound (406 mg, yield 94%) as a colorless oil.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[CH:28][N:27]=2)=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[CH2:35]([NH2:38])[CH2:36][CH3:37].C(N(CC)CC)C>O1CCOCC1.O>[CH:28]1[N:27]=[C:26]([C:24]([C:21]2[CH:22]=[CH:23][C:14]([NH:13][C:5](=[O:11])[NH:38][CH2:35][CH2:36][CH3:37])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:25])[N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=12
Reactant: CCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccccn23)ccc1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCNC(=O)Nc1ccc(C(=O)c2ncc3ccccn23)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
0.35 g (1.2 mmol) of triphosgene is added, at ambient temperature under a nitrogen atmosphere, to a suspension of 0.5 g (1.7 mmol) of methyl 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml of anhydrous dioxane. After heating for 2 hours at 100° C., 0.28 ml (3.4 mmol) of n-propylamine and then 0.71 ml (5 mmol) of triethylamine are added to the reaction medium at ambient temperature. After stirring for 18 hours at ambient temperature, H2O is added. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered, and concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (98/2) mixture. 0.410 g of a yellow solid is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6].[CH3:33]I.O>CN(C)C=O>[CH2:3]([O:7][C:8]1[C:13]([CH2:14][O:15][CH3:33])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (11 mg 4.5 mMol) is added to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-3-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]pyridine (Example 29) (128 mg, 0.3 mMol) in dimethylformamide (50 mL). After 1 hour, methyl iodide (85 mg, 0.6 mMol) is added and the reaction mixture is stirred for 20 hours at room temperature. Water (1 mL) is added dropwise and the mixture is concentrated to an oily solid. The titled material is purified by silica gel chromatography.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=4)[C:15]3=[O:30])[CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6]1)=[O:4].[CH3:33][NH:34][CH3:35]>O1CCCC1>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][N:16]2[C:17]([CH3:21])([CH3:20])[C:18](=[O:19])[N:14]([C:11]3[CH:12]=[C:13]4[C:8]([C:7]([CH3:31])([CH3:32])[CH2:6][N:5]4[C:3](=[O:4])[CH2:2][N:34]([CH3:35])[CH3:33])=[CH:9][CH:10]=3)[C:15]2=[O:30])[CH:28]=[CH:27][N:26]=1
Reactant: CNC
Reactant: CC1(C)CN(C(=O)CCl)c2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21

Procedure:
A solution of 0.951 g of 3-[1-(chloroacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage j) of Example 3 in 80 mL of a 2M solution of dimethylamine in tetrahydrofuran is heated at 60° C. for 4 hours. The reaction mixture is then concentrated under reduced pressure and is triturated in 30 mL of water. A solid forms, which is filtered off, washed with twice 5 mL of diisopropyl ether and dried to give 3.5 g of 1-[(2-chloropyridin-4-yl)methyl]-3-[1-(N,N-dimethylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [C:1](N1C=CN=C1)(=[O:9])[C:2](N1C=CN=C1)=[O:3].[CH3:15][N:16]1[C:20]([NH:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19](N)[CH:18]=[N:17]1.[NH:42]([CH2:53][CH2:54][NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49].C(OCC)(=O)C>CN(C)C=O.C(Cl)Cl>[CH3:15][N:16]1[C:20]([NH:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:19]([C:1](=[O:9])[C:2]([N:42]([CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])[CH2:53][CH2:54][NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:3])[CH:18]=[N:17]1
Reactant: O=C(C(=O)n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Reactant: Cn1ncc(N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc(C(=O)C(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solusion of 1,1′-oxalyldiimidazole (1.52 g) in N,N-dimethylformamide (16 ml) was added 1-methyl-N5-trityl-1H-pyrazole-4,5-diamine (1.42 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a solution of di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (4.55 g) in N,N-dimethylformamide (4 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 day and then allowed to stand at room temperature for 9 days. To the reaction mixture were added ethyl acetate (50 ml) and methylene chloride (20 ml). The resulting precipitate was collected by filtration and dried in vacuo to give di-tert-butyl [({2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-oxoacetyl}imino)bis(2,1-ethanediyl)]biscarbamate (1.79 g) as a solid. The mother liquor was washed successively with water, 5% aqueous citric acid solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crystalline residue was washed with a mixed solvent of methylene chloride and diethyl ether, dried in vacuo and combined with the former solid to give di-tert-butyl [({2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-oxoacetyl}imino)bis(2,1-ethanediyl)]biscarbamate (2.44 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])(=[O:20])=[O:19])[CH2:13]1)[OH:11].[H][H].CS(O[CH2:34][CH2:35][CH2:36][O:37][CH3:38])(=O)=O>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:11][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:20])[CH2:13]1
Reactant: C[Si](C)(C)CCS(=O)(=O)N1CCCC(C(O)c2ccccc2Br)C1
Reactant: COCCCOS(C)(=O)=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCOC(c1ccccc1Br)C1CCCN(S(=O)(=O)CC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
A 250-mL three neck flask fitted with a reflux condenser was charged with NaH (60% in mineral oil, 644 mg of material, 16.1 mmol, 5.0 equiv). Anhydrous THF (80 mL) was added. A solution of (2-bromophenyl)(1-(2-(trimethylsilyl)ethanesulfonyl)piperidin-3-yl)methanol (1.4 g, 3.22 mmol, 1.0 equiv) in 10 mL of THF was slowly added via syringe. After cessation of hydrogen evolution, a solution of 3-methoxypropyl methanesulfonate (2.2 g, 12.8 mmol, 4.0 equiv) in 10 mL of THF was added and the resulting mixture was heated to reflux. After 1.0 h the signals for the starting material in the LC-MS were consumed and a new peak with M+Na for the desired product was observed. The mixture was allowed to cool to rt and excess NaH was quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with brine and purified by flash chromatography on silica gel (40 g) eluting with 0-25% EtOAc in hexanes. This afforded 3-((2-bromophenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine (1.2 g, 73%) as a clear syrup containing a mixture of two diastereomers. No attempt was made to separate the diastereomers. MS ESI +ve m/z 506 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=O.[CH3:11][O:12][C:13](=[O:20])[C@@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>>[CH3:11][O:12][C:13](=[O:20])[CH:14]([NH:15][C:8](=[O:10])[CH:7]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: O=C(O)C=Cc1cccs1
Product: COC(=O)C(CC(C)C)NC(=O)C=Cc1cccs1

Procedure:
Prepared in a similar manner as described in example 4 from 3-thiophen-2-yl-acrylic acid and D-leucine methyl ester. MS (M+H, 282.2).
Reaction SMILES: [F:1][C:2]([C:14](OC)=[O:15])=[CH:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]([CH2:14][OH:15])=[CH:3][C:4]1([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)C(F)=CC1(c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=CC1(c2ccc(F)cc2)CC1
Yield: 89.9 %

Procedure:
The method of Example 9 was repeated using 1-(2-fluoro-2-(methoxycarbonyl)ethenyl)-1-(4-fluorophenyl)-cyclopropane (Example 4) (0.29 g), diethyl ether (10 ml) and lithium aluminium hydride (0.11 g) to yield the title compound (0.23 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:15](Cl)(Cl)=[O:16]>O>[CH3:12][O:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:15](=[O:16])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cccc(N)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2[nH]c(=O)oc(=O)c12

Procedure:
A solution of 2-amino-6-methoxybenzoic acid (10 g, 60 mmol), water (330 mL), and sodium hydroxide (7.2 g, 176 mmol) was treated with phosgene (20% solution in toluene, 82 mL, 164 mmol) over 1 hour and filtered. The filter cake was dried to provide the desired product. MS (ESI(+)) m/e 194 (M+H)+, 211 (M+NH4)+, 216 (M+Na)+; (ESI(−)) m/e 192 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.64 (t, 1H), 6.84 (d, 1H), 6.68 (d, 1H), 3.88 (s, 3H).