Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.[OH-].[Na+]>COCCOCCOC>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CC(C)(C)c1ccccc1N1CCNCC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of 2-tert-butylaniline (35.7 g, 0.240 mol) and di(2-chloroethyl)amine hydrochloride (47.0 g, 0.264 mol) in diethylene glycol dimethyl ether (350 mL) was refluxed for 12 h. Then the mixture was cooled to room temperature, and 2 M NaOH solution (50 mL) was added. The mixture was extracted with ether, the combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude product as a colorless oil. The product was purified by re-crystallization in petroleum ether to afford 1-[2-(tert-butyl)phenyl]piperazine (22.6 g, 43%) as a white solid. To the mixture of [2-(tert-butyl)phenyl]piperazine and ethyl acetate was added dropwise 4 M HCl solution in ethyl acetate (50 mL), keeping stirring for 0.5 h. Then the resulting solid was collected by filtration to give 1-[2-(tert-butyl)phenyl]piperazine dihydrochloride (30 g, quant.) as a white solid, which was re-crystallized in ethanol to give 1-(2-tert-butylphenyl)piperazine dihydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>O.CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[NH:27][N:26]=[N:25][N:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cc(OCCCCCCC#N)cc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(OCCCCCCc2nnn[nH]2)cc(C(C)(C)C)c1O
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of 4.0 g (12.1 mmole) of 7-(3,5-di-t-butyl-4-hydroxyphenoxy)heptanenitrile (from Example 3), 2.35 g (36.2 mmole) sodium azide, 1.94 g (36.2 mmole) of ammonium chloride, 0.51 g (12.1 mmole) of lithium chloride and 50 ml of N,N-dimethylformamide was heated in a stoppered flask at 120° C. for 48 hours. To this mixture was added 2.35 g (36.2 mmole) of sodium azide and 1.94 g (36.2 mmole) of ammonium chloride, and heating was continued for an additional 48 hours. The reaction mixture was poured into water and extracted twice with chloroform. The chloroform extracts were combined, washed with water, dried with magnesium sulfate and evaporated to give the crude product as a dark oil. This oil was purified by four recrystallizations from a mixture of ethyl acetate and hexane, followed by silica gel chromatography eluting with a mixture of chloroform/methanol/acetic acid in a ratio of 98/2/0.25. After three further recrystallizations, 0.92 g of 5-[6-(3,5-di-t-butyl-4-hydroxyphenoxy)hexyl]-tetrazole, m.p. 128°-131° C., was obtained as a white solid. Analysis: Calculated for: C21H34N4O2 : %C, 67.4; %H, 9.2; %N, I5.0; Found %C, 67.4; %H, 9.3; %N, 15.2.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH3:74])=[CH:68][CH:67]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:46][CH2:47][C@H:42]([C:38]([CH3:39])([CH3:41])[CH3:40])[CH2:43][CH2:44]3)[C:50]=2[C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH3:74])=[CH:68][CH:67]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CCOc1ccc(-c2c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc3cc([C@]4(C)COC(=O)N4)ccc23)cc1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CCOc1ccc(-c2c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc3cc([C@@](C)(N)CO)ccc23)cc1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 35% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS; m/z=459.45 [M-16]+. 1H NMR (MeOD) δ: 7.91-7.95 (m, 1H), 7.83-7.88 (m, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.44-7.49 (m, 1H), 7.37 (s, 1H), 7.19-7.26 (m, 2H), 7.01-7.07 (m, 2H), 4.10-4.19 (m, 2H), 3.98-4.07 (m, 1H), 3.73 (d, J=10.8 Hz, 1H), 3.69 (d, J=11.0 Hz, 1H), 1.97-2.04 (m, 2H), 1.75-1.82 (m, 2H), 1.52 (s, 3H), 1.48 (t, J=6.9 Hz, 3H), 1.14-1.23 (m, 2H), 0.96-1.12 (m, 3H), 0.87 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Clc1ccc(I)cn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2ccccc2)cn1
Yield: 70.5 %

Procedure:
A mixture of 2-chloro-5-iodopyridine (5.0 g, 20.9 mmol), phenylboronic acid (2.6 g, 20.9 mmol), Pd(Ph3P)4 (1.45 g 1.25 mmol), sodium carbonate (6.64 g, 62.6 mmol), DME (20 mL) and water (5 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then vacuum distilled to give 2-chloro-5-phenylpyridine (2.79 g, 14.71 mmol (70.5% yield).
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9](CCOC3C=CC=CC=3)[C:8]2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.CN1C=CC=C1CN>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:9][CH2:10][C:11]4[N:7]([CH3:8])[CH:5]=[CH:6][CH:2]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cn1cccc1CN
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccn1C
Yield: 26 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1-methyl-1H-pyrrol-2-yl)methanamine, the title compound was obtained as a colorless solid in 26% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 2H), 6.61 (s, 1H), 6.13-6.03 (m, 3H), 5.71 (t, J=4.6 Hz, 1H), 4.55 (d, J=4.6 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.61 (s, 3H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=[C:4]3[CH:3]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][C:33]=3[Cl:35])[N:7]=2)=[N:13][CH:14]=1)#[N:19]
Reactant: CCOC(=O)c1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C(=O)O)cn23)nc1
Temperature: 120 °C

Procedure:
1 g (2.59 mmol) of ethyl 7-chloro-5-({2-[(5-cyanopyridin-2-yl)amino]ethyl}amino)imidazo[1,2-c]pyrimidine-2-carboxylate (Example 59A), 580 mg (2.98 mmol) of (2,4-dichlorophenyl)boronic acid and 716 mg (5.18 mmol) of potassium carbonate are introduced into a mixture of 25 ml of 1,2-dimethoxyethane and 10 ml of water under argon, and the mixture is carefully degassed before 300 mg (0.26 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated at 120° C. for 16 h. Filtration and subsequent purification by preparative HPLC result in 185 mg (14% of theory) of the product as a solid.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[NH2:10][C:11]1[CH:12]=[C:13]([C:21]([O:23]C)=O)[CH:14]=[C:15]([C:17]([O:19]C)=O)[CH:16]=1.O>C(Cl)Cl>[N:5]1([C:21]([C:13]2[CH:12]=[C:11]([CH:16]=[C:15]([C:17]([N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[O:19])[CH:14]=2)[NH2:10])=[O:23])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: O
Product: Nc1cc(C(=O)N2CCCC2)cc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of AlMe3 (2M in toluene, 19.5 mL, 2 eq) was added dropwise to a solution of pyrrolidine (3.25 mL, 2 eq) in 50 mL of anhydrous DCM at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. 1,3-Dimethyl 5-aminobenzene-1,3-dicarboxylate (4.10 g, 19.5 mmol) was added and the reaction mixture was refluxed for 38 h. The mixture was then poured in ice cooled water and filtered. The aqueous filtrate was extracted with CHCl3. The combined organic layers were dried over MgSO4, filtered and evaporated to give 3.5 g of expected compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[CH:5]=[O:6].C([BH3-])#N.[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1
Reactant: O=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: OCc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Yield: 100.5 %

Procedure:
A solution of 3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-benzaldehyde (0.065 g, 0.19 mmol) in DCM (0.5 mL), MeOH (0.5 mL) and acetic acid (0.5 mL) was treated with sodium cyanoborohydride (0.013 g, 0.21 mmol) and the resultant mixture was stirred for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired compound as an off-white solid (0.066 g, quant. yield). 1H NMR (300 MHz, CDCl3): δ 8.52 (d, J=5.6 Hz, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.49 (s, 2H), 4.79 (s, 2H).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:12]=2[N:13]=1.[CH2:23]([SH:25])[CH3:24].O>CN1C(=O)CCC1>[CH2:23]([S:25][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:12]=2[N:13]=1)[CH3:24]
Reactant: CCS
Reactant: FC(F)(F)Sc1ccc2oc(-c3sccc3Br)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCSc1ccsc1-c1nc2cc(SC(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.31 g of sodium hydride (60%) was added to 20 ml of a solution of 2.76 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethylthio)benzoxazole and 0.6 ml of ethanethiol in NMP at 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 2.65 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethylthio)benzoxazole (Compound of Present Invention (30)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH:11]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: O=C1C(C2CCCCC2)CCN1Cc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-(3-cyclohexyl-2-oxo-pyrrolidin-1-ylmethyl)-phenyl ester (0.80 g, 1.69 mmol), 4-methoxycarbonylphenylboronic acid (0.457 g, 2.53 mmol), sodium carbonate (0.538 g, 5.07 mmol) in THF (20 mL) and water (5 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.098 g, 0.084 mmol), raise the reaction temperature to 80° C., and stir for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 20% ethyl acetate in hexanes to afford 0.62 g (80%) of the titled product. MS (m/z): 460 (M+).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=2)[CH2:3]1.[OH-:20].[Na+].OO>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:17])=[O:20])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=2)[CH2:3]1
Reactant: [OH-]
Reactant: CSc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(C(N)=O)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
4-((1R,3R,4R)-3-Hydroxy-4-methylcyclohexylamino)-2-(methylthio)pyrimidine-5-carbonitrile (0.335 g, 1.203 mmol; synthesis described herein) was dissolved in DMSO (3 mL). Then aqueous sodium hydroxide solution (1.003 mL, 6 M, 6.02 mmol) and aqueous hydrogen peroxide solution (0.682 mL, 6.02 mmol, 30%) were added at room temperature. Then the reaction mixture was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and it was poured into 100 mL of ice water. The white precipitate was collected and was washed twice with water. The solid was dried to give 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (0.260 g, 0.877 mmol, 72.9% yield); MS (ESI) m/z 297.7 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:13])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[CH2:3][OH:4].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O.C(Cl)Cl>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:4][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)([F:13])[F:1]
Reactant: COc1cccc(C(F)(F)CO)c1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(F)(F)COCCCCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of Intermediate 68 (3.19 g, 16.95 mmol) in dimethylformamide (20 mL) was added 60% sodium hydride (1.36 g, 33.9 mmol) and 1,6-dibromohexane (5.2 mL, 33.9 mmol). The mixture was stirred at room temperature for 2 hours. The crude was diluted with methylene chloride (50 mL) and washed with water (3×50 mL), dried (MgSO4) and concentrated. The excess of 1,6-dibromohexane was eliminated by distillation at reduced pressure (P=0.15-0.18 mmHg, T=60-65° C.) and the crude was purified by column chromatography with silica gel using methylene chloride as eluent. The title compound was obtained (3.41 g, 57%) as oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=O)[CH2:9][CH:10]=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:38][NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(OCC)(=O)C.C1COCC1>[CH2:40]([N:39]([CH3:38])[C:13](=[O:15])[C@@H:12]([N:8]([CH2:9][CH:10]=[CH2:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CNCc1ccccc1
Reactant: C=CCN(C(=O)OC(C)(C)C)C(Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: -22 °C
Reaction time: 2 h

Procedure:
Combine (S)-2-[N-(t-butoxycarbonyl)-allylamino-3-phenyl-propionic acid (11.1 g, 36.35 mmol), and THF (360 mL). Cool to -22° C. Add N-methylmorpholine (7.09 mL, 54.53 mmol) and then stir for 10 minutes. Add isobutyl chloroformate (7.09 mL, 54.53 mmol) and stir for 30 minutes at -22° C. Add N-methyl-N-benzylamine (7.09 mL, 54.53 mmol). Allow to warm to ambient temperature and stir for 2 hours. Dilute the reaction mixture with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 10% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:30][C:31]1[C:32]([F:50])=[CH:33][C:34]([OH:49])=[C:35]([C:37]2[CH:38]=[N:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:41]=2)[CH:36]=1>>[Cl:30][C:31]1[C:32]([F:50])=[CH:33][C:34]([O:49][C:8]2[CH:7]=[CH:6][C:5]([S:10]([N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:14]3[S:18][N:17]=[CH:16][N:15]=3)(=[O:11])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])=[C:35]([C:37]2[CH:38]=[N:39][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH:41]=2)[CH:36]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(Cl)c(F)cc2O)cn1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3cc(F)c(Cl)cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared using a method analogous to that for Preparation 733 below, using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68) and tert-butyl 4-(5-chloro-4-fluoro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate (Preparation 743). Purification was by column chromatography (silica, heptane-ethyl acetate 10-60% v/v).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1cccc(C(F)(F)F)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example 33, 27.5 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[3-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[C@@H:12]([CH3:16])[C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H]1NCCN(CCCc2ccccc2)[C@H]1C
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: C[C@H]1[C@H](C)N(C(=O)c2ccco2)CCN1CCCc1ccccc1

Procedure:
The compound was obtained by following the same process as in Example 3 from a mixture of trans-1-(3-phenylpropyl)-2,3-dimethylpiperazine [b.p. 130° - 132°C (2 mmHg), dipicrate, m.p. 195° - 196°C], 2-furoyl chloride and benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:31])([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[CH:14]=[CH:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:32]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[C:14]([I:32])=[CH:13]2)([CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4ccn(C5(C)CN(C(=O)OC(C)(C)C)C5)c4cc3N21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)NN=C2COc3cc4c(I)cn(C5(C)CN(C(=O)OC(C)(C)C)C5)c4cc3N21
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
To a solution of 3-methyl-3-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (Example #148, Step J, 1 g, 2.35 mmol) in THF (20 mL) was added 1-iodopyrrolidine-2,5-dione (0.582 g, 2.59 mmol) in portions at −5-0° C. The reaction mixture was stirred at 0° C. for 3 h. Saturated aqueous sodium sulphite solution (5 mL) was added to quench the reaction and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10%˜100% EtOAc in petroleum ether) to give 3-((R)-8-iodo-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.4 g, 30%) as a yellow solid. 1H NMR (400 MHz, methanol-d4): δ 7.39 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 4.97 (m, 1H), 4.53 (d, J=8.5 Hz, 2H), 4.59 (m, 2H), 4.54 (m, 2H), 4.29 (m, 2H), 1.81 (s, 3H), 1.51-1.48 (m, 12H). LC/MS (Table 1, Method 2) Rt=1.279 min.; MS m/z: 552 [M+H]+.