Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Nc1ccccc1C1(O)CCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2ccccc2Nc2nc(Cl)ncc2Cl)CCC1
Temperature: 85 °C

Procedure:
1-(2-Aminophenyl)cyclobutanol (56 mg, 0.343 mmol), 2,4,5-trichloropyrimidine (40 μl, 0.349 mmol) and N,N-diisopropylethylamine (120 μl, 0.694 mmol) were suspended in 2-propanol (1.5 mL) in a sealed tube, and the solution was heated to 85° C. for 4 hours. The reaction mixture was partitioned between H2O (15 mL) and CH2Cl2 (3×15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (Analogix, 0 to 25% ethyl acetate-hexanes over 25 minutes, 4 g silica, 18 mL/minute) to give the title compound.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(C)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(Cl)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.28 mmol) was added to a stirred solution of [6-chloro-3-methyl-4-(4-p-tolylsulfamoyl-phenyl)-naphthalen-2-yl]-acetic acid methyl ester (0.035 g, 0.07 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded [6-chloro-3-methyl-4-(4-p-tolylsulfamoyl-phenyl)-naphthalen-2-yl]-acetic acid (0.03 g, 88%) as a solid. 1H NMR (DMSO-d6) δ: 12.48 (br. s, 1H), 10.09 (s, 1H), 7.77-8.05 (m, 4H), 7.33-7.56 (m, 3H), 6.95-7.16 (m, 4H), 6.82 (s, 1H), 3.84 (s, 2H), 2.21 (s, 3H), 2.02 (s, 3H). MS calcd. for C26H21ClNO4S [(M−H)−] 478, obsd. 478.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([C:12]1[CH:13]=[C:14]([OH:20])[C:15]([OH:19])=[CH:16][C:17]=1[CH3:18])(=[O:11])=[O:10].C([O:23][C:24](=[O:28])[CH:25](Cl)Cl)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]2[O:19][CH:25]([C:24]([OH:28])=[O:23])[O:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc2c(cc1S(=O)(=O)c1cc(Cl)ccc1Cl)OC(C(=O)O)O2
Reaction time: 18 h

Procedure:
In a manner analogous to that described in Example 4, 21.3 g (64 mmol) of 4-(2,5-dichlorophenylsulphonyl)-5-methyl-1,2-benzenediol, 10.0 g (64 mmol) of dichloroacetic acid ethyl ester and 44.2 g (320 mmol) of potassium carbonate in 160 ml of 1,2-dimethoxyethane are boiled under reflux. After 18 hours, the reaction mixture is filtered and the solid filtration residue is washed twice with 1,2-dimethoxyethane. 44 g of fresh potassium carbonate and 10 g of dichloroacetic acid ethyl ester are added to the combined organic solutions and the whole is stirred for 5 minutes using a high-speed stirrer and boiled, while stirring normally, for a further 17 hours. Working up is carried out in a manner analogous to that described in Example 10. After drying carefully, 5-(2,5-dichlorophenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained in the form of white crystals having a melting point of 155°-157° (from diisopropyl ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([SH:12])[N:6]=[C:5]2[OH:13].CI.[O-][CH2:17]C.[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:17])[N:6]=[C:5]2[OH:13]
Reactant: CC[O-]
Reactant: Oc1nc(S)nc2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc(O)c2cc(Br)ccc2n1

Procedure:
A solution of 6-bromo-2-mercapto-quinazolin-4-ol (0.32 g, 1.26 mmol), methyl iodide and sodium ethoxide in DMF (5 mL) was stirred at room temperature for 3 hours. HCl (1N, 3 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to provide 0.31 g of crude product which was used without further purification. The product was characterized as follows: MS (m/z) 271 [M+H]+; HPLC retention time (Rt)=1.87 minutes (Method B).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[CH:22]([C@@H:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:33]#[N:34])[CH:30]=2)[CH2:25]1)=O>>[OH:21][C:18]([C:9]1[N:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:22][C@@H:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:33]#[N:34])[CH:30]=4)[CH2:25]3)[CH2:7][CH2:6]2)[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=1)([CH3:19])[CH3:20]
Reactant: N#Cc1ccc2c(c1)C[C@@H](C=O)C2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCC(N)CC1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of 2-[1-(4-amino-cyclohexyl)-5-methyl-1H-benzoimidazol-2-yl]-propan-2-ol (prepared as cis/trans-isomer mixture) and (S)-2-formyl-indan-5-carbonitrile through the same reductive amination method described previously. The crude mixture was separated through flash column chromatography using methylene chloride and methanol (20:1 to 10:1). The fraction with less retention time (higher Rf) gave cis-(S)-2-({4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazole-1-yl]-cyclohexylamino}-methyl)-indan-5-carbonitrile. The analysis of the 1H-NMR confirmed the cis-conformation of the cyclohexane. LC-MS showed a single peak, C28H34N4O (m/e) calcd 442.2733, obsd 443.3 (M+H). 1H-NMR (CD3OD) □ 7.82 (d, 1H), 7.55 (s, 1H), 7.49 (d, 1H), 7.41 (s, 1H), 7.38 (d, 1H), 7.03 (d, 1H), 5.30 (m, 1H), 3.23 (m, 2H), 2.71-2.93 (m, 8H), 2.43 (s, 3H), 1.98 (br d, 2H), 1.72 (s, 6H), 1.64 (m, 4H).
Reaction SMILES: [N:1]1([C:6]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[C:13]1([CH:11]([C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9][CH2:10]2)[NH2:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCCC2)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: CO
Solvent: C1CCOC1
Product: NC(c1ccccc1)C1(N2CCCC2)CCCC1
Yield: 56 %

Procedure:
The title compound (0.55 g, 56%) was prepared from 1-(1-pyrrolidinyl)cyclopentane carbonitrile D9 (0.66 g, 4 mmol), and phenyllithium in dibutylether (2.4 ml of a 1.8M solution; 4.4 mmol) in THF (4 ml), followed by reaction with sodium borohydride (0.456 g, 12 mmol) in methanol (4 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.41 (1H, m), 1.17 (1H, m), 1.35 (2H, m), 1.60 (2H, m), 1.73 (5H, m), 1.84-2.02 (3H, m), 2.64-2.74 (4H, m), 4.27 (1H, s), 7.21-7.31 (3H, m), 7.48 (2H, m).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:11]([OH:13])[OH:12])=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].Cl>O.CCOC(C)=O>[N+:14]([CH:17]([CH:3]1[O:13][B:11]([OH:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2)[CH3:18])([O-:16])=[O:15]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C1OB(O)c2ccccc21)[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
A solution of NaOH (1.6 g, 41 mmol) in H2O (20 mL) was added to 2-formyl phenylboronic acid (5.1 g, 34 mmol) at rt. The mixture was stirred for 15 min then nitroethane (2.9 mL, 41 mmol) was added dropwise. The mixture was stirred for 30 min and then the clear reaction solution was acidified with 2 N HCl and EtOAc was added. The organic layer was separated, washed with H2O then brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (2:1 hexane/EtOAc) gave the title compound as a colorless oil: yield 6.72 g (quantitative).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][O:20][CH2:21][CH:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>O1CCCC1.CCOCC>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][CH:26]1[CH2:27][CH:22]([CH2:21][O:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:24][C:25]1=[O:28]
Reactant: BrCc1ccccc1Br
Reactant: O=C1CCC(COCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1CCC(COCc2ccccc2)CC1Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 6 h
Yield: 23 %

Procedure:
To a 0° C. of N,N-diisopropylamine (6.1 ml, 43.4 mmole) in dry tetrahydrofuran (50 ml) was added n-butyllithium (1.6M in hexane), (27 ml, 43.4 mmol). This solution was added slowly to a cold (-78° C.) solution of the product of Example 107. After stirring 30 minutes a solution of 2-bromobenzyl bromide (8.3 g, 33.4 mmol) was added. The mixture stirred for 6 hours at 0° C. and was poured onto water. The organics were layered with ether (500 ml). The ether layer was dried (MgSO4), concentrated in vacuo, then chromatographed to give 2.94 g (23% yield) of the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C1(C)C(C)=CC=CC=1.[C:17]([CH2:25][C:26](S)=[S:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1>O>[C:18]1([C:17]2[CH2:25][C:26](=[S:27])[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: O=C(CC(=S)S)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1C
Product: S=C1CC(c2ccccc2)=Nc2ccccc2N1

Procedure:
A mixture of 1.08 g of o-phenylendiamine, 10 ml of xylene and 1.96 g of benzoyldithioacetic acid (Thuillier et al - Bull. Soc. Chim. Fr. 1938 (1959) is refluxed for 1 hour under a stream of nitrogen. The reaction may also be carried out in water, alcohol or dioxane. After cooling, the precipitate is filtered, washed with ethyl ether, and crystallized from ethyl acetate. Yield 2 g, m.p. 228°-230°C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:19][C:20]1[CH:21]=[CH:22][C:23](/[C:28](/[C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH3:43])[CH:37]=2)=[CH:29]/[C@@H:30]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31]2)=[N:24][C:25]=1[O:26][CH3:27].O>CN(C)C=O>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][O:42][C:39]1[CH:40]=[CH:41][C:36](/[C:28](/[C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([O:26][CH3:27])[N:24]=2)=[CH:29]\[C@@H:30]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31]2)=[CH:37][C:38]=1[CH3:43])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(O)c(C)c2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(C)c2)ccc1Cl
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (470 mg) and (3-bromopropoxy)-tert-butyldimethylsilane (600 μL) were sequentially added to a solution of (5R)-5-[(E)-2-(5-chloro-6-methoxypyridin-2-yl)-2-(4-hydroxy-3-methylphenyl)ethenyl]pyrrolidin-2-one obtained in Example 4-50(2) (610 mg) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 15 hours and at 65° C. for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:4→2:8) to give (5R)-5-[(E)-2-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-methylphenyl]-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous (879 mg, 97%).
Reaction SMILES: O.[ClH:2].[C:3]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][C:31]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:34]#[N:35])[CH2:30][CH2:29]2)([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CCO.[Ni]>[OH2:10].[ClH:23].[ClH:2].[NH2:35][CH2:34][C:31]1([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][C:13]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:14][CH2:15][CH2:16][N:11]([C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)[CH2:29][CH2:30]1.[NH2:35][CH2:34][C:31]1([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][C:13]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:14][CH2:15][CH2:16][N:11]([C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)[CH2:29][CH2:30]1.[ClH:23].[ClH:23]
Reactant: N#CC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: O
Product: NCC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Reaction time: 72 h
Yield: 111.8 %

Procedure:
A mixture of 2.3 g of the compound obtained in EXAMPLE 8 and 0.3 g of Raney® nickel in 100 ml of EtOH is hydrogenated for 72 hours at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (85/15; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.08 g of the expected product.
Reaction SMILES: NC1CCN(C(OC(C)(C)C)=O)CC1.[Cl:15]C(OC1C=CC=CC=1)=O.N1(CCC2C=CC([N:38]3[CH2:43][CH2:42][CH:41]([NH:44][C:45]([N:47]4[CH2:52][CH2:51][C:50](=[CH:53][C:54]5[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:55]=5[F:61])[CH2:49][CH2:48]4)=[O:46])[CH2:40][CH2:39]3)=CC=2)C=CN=N1.CCN(CC)CC>C(#N)C.O>[ClH:15].[F:61][C:55]1[CH:56]=[CH:57][C:58]([F:60])=[CH:59][C:54]=1[CH:53]=[C:50]1[CH2:51][CH2:52][N:47]([C:45]([NH:44][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)=[O:46])[CH2:48][CH2:49]1
Reactant: O=C(NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1)N1CCC(=Cc2cc(F)ccc2F)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NC1CCNCC1)N1CCC(=Cc2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Amino-N-Boc-piperidine (5.00 g, 24.9 mmol) was dissolved in acetonitrile (100 mL), and phenyl chloroformate (3.46 mL, 27.4 mmol) was added dropwise thereto at 0° C., followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was dissolved in acetonitrile (50 mL), and the compound (2.88 g, 11.7 mmol) obtained in Example 34 (1) and Et3N (3.70 mL, 26.4 mmol) were added thereto, followed by stirring at 60° C. overnight. Water was added to the reaction mixture and the precipitate was collected by filtration, thereby giving tert-butyl 4-(4-(2,5-difluorobenzylidene)piperidine-1-carboxamido)piperidine-1-carboxylate (4.10 g, 38%) as a white solid. Following the procedure of Example 34 (1) and using this tert-butyl compound in place of tert-butyl 4-(2,5-difluorobenzylidene)piperidine-1-carboxylate, the title compound (quant.) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:8]1[C:7]([OH:12])=[C:6]([CH3:13])[CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2.[BrH:14]
Reactant: Cc1ccc2cc(O)c(C)cc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Cc1ccc2c(Br)c(O)c(C)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,7-dimethylquinolin-6-ol (200 mg, 1.2 mmol) in acetic acid (10 mL) was added Br2 (0.062 mL, 1.21 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 0.5 hour. The solid formed was filtered and collected, washed with 2 mL of acetic acid to give 5-bromo-2,7-dimethylquinolin-6-ol as an HBr salt. LCMS-ESI+ (m/z): [M+H]+ calc'd for C11H11BrNO: 251.99; Found: 252.2, 254.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:30]2)=[CH:34][CH:35]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: COc1ccc(CC2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methoxybenzyl)pyrrolidine oxalate (16.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.5 mg). Calcd for C23H24N2O3: 376.1787, found 376.1801.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1ccc(Cl)cc1
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(Cl)cc1

Procedure:
Boiling a solution of 7.1 g of 4-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 8 hours yields 2-amino-4-(4-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 130°-132°C (ethyl acetate/petroleum ether).
Reaction SMILES: BrC1C=C2C(=CC=1)C(=O)N([C@H](C(C)C)C(OC)=O)C2.[Br:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([CH2:31]Br)[CH:22]=1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[Br:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:29][CH:30]=1)[C:25](=[O:27])[N:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CCOC(=O)CCN
Agent: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: Cl
Product: CCOC(=O)CCN1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 377 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and ethyl 3-aminopropanoate hydrochloride.
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[O:16][C:17](=[O:64])[CH:18]([NH:33][C:34]([NH:36][CH:37]([C:52]([O:54]CC2C=CC(OC)=CC=2)=[O:53])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[O:35])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC(OC)=CC=2)=[O:22])=CC=1>C(O)(C(F)(F)F)=O>[C:52]([CH:37]([NH:36][C:34](=[O:35])[NH:33][CH:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:17]([OH:64])=[O:16])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)([OH:54])=[O:53]
Reactant: COc1ccc(COC(=O)CCC(NC(=O)NC(CCCCNC(=O)c2ccc(F)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1ccc(F)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.3 %

Procedure:
A solution of 3% anisole in TFA (15 mL) was added to 5 (0.081 g, 0.1 mmol) at 0° C. The mixture was stirred at room temperature for 20 min then concentrated on a rotary evaporator. The crude material was purified by HPLC (Econosil C18 10 μm, 250×10 mm, H2O/CH3CN/TFA (75/25/0.1), 4 mL/min, with purified 6 eluting at about 9 min) to afford 0.035 g (79%) of 6. 1H-NMR (400 MHz, D2O) δ 7.66-7.69 (m, 2H), 7.11-7.16 (m, 2H), 4.12-4.19 (m, 2H), 3.28-3.31 (m, 2H), 2.39-2.43 (m, 2H), 2.07-2.09 (m, 1H), 1.79-1.90 (m, 2H), 1.55-1.69 (m, 3H), 1.39-1.40 (m, 2H). ESI-Mass calcd for C19H24FN3O8Na [M+Na]+ 464.1. found 464.4. FAB-HRMS calcd for C19H25FN3O8 [M+H]+ 442.1626. found 442.1646.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.[H-].[Na+]>CN1CCCC1=O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=2)[CH:10]=1
Reactant: Nc1nccnc1Cl
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1nccnc1OCc1cccnc1
Yield: 79.7 %

Procedure:
Prepared as for Example 121a using 3-chloro-2-aminopyrazine (0.5 g), pyridine-3-methanol (0.42 g) and sodium hydride (0.31 g of a 60% dispersion in oil) in N-methylpyrrolidinone (5 mL) to afford the sub-titled compound as a solid (0.62 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:14])[N:3]=1.[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[Cl:14][C:4]1[C:5]([CH2:9][C:10]([F:13])([F:12])[F:11])=[C:6]([O:16][CH3:15])[N:7]=[C:2]([O:19][CH3:18])[N:3]=1
Reactant: C[O-]
Reactant: FC(F)(F)Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CO
Agent: [Na+]
Product: COc1nc(Cl)c(CC(F)(F)F)c(OC)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 2,4,6-trichloro-5-(2,2,2-trifluoro-ethyl)-pyrimidine (0.633 g, 2.39 mmol) in methanol (20 mL) at 0° C. was added sodium methoxide (25 wt %, 1.09 mL, 4.77 mmol). The reaction mixture was warmed to room temperature overnight. The reaction mixture was concentrated, dissolved in ethyl ether and washed with water. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexane) to give a colorless oil (0.5531 g, 90%). 1H NMR (300 MHz, CDCl3): δ 3.87 (s, 3H), 3.83 (s, 3H), 3.32 (q, J=10.2 Hz, 2H); Mass spectrum: 257.1, 259.1 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]3[O:44][C:43]([C:45]([O:47][CH2:48]C)=[O:46])=[CH:42][C:41]=3[CH:50]=2)O1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[CH:39][C:40]4[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][C:41]=4[CH:50]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2o1
Product: COC(=O)c1cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)ccc2o1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (9 mg, 0.02 mmol; from step 6) and ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-carboxylate. LCMS (M+H)+: m/z=466.2.