Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([C@:20]1(O)[C:48]2[CH:47]=[C:46]3[N:26]([CH2:27][C:28]4[C:29]3=[N:30][C:31]3[C:32]5[C:33]=4[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:35]=[N:36][C:37]=5[CH:38]=[CH:39][CH:40]=3)[C:25](=[O:49])[C:24]=2[CH2:23][O:22][C:21]1=[O:50])[CH3:19].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]([O:17][C@@:20]1([CH2:18][CH3:19])[C:48]2[CH:47]=[C:46]3[N:26]([CH2:27][C:28]4[C:29]3=[N:30][C:31]3[C:32]5[C:33]=4[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:35]=[N:36][C:37]=5[CH:38]=[CH:39][CH:40]=3)[C:25](=[O:49])[C:24]=2[CH2:23][O:22][C:21]1=[O:50])=[O:16])[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(=O)O)C(=O)CNC(=O)OC(C)(C)C
Reactant: CCCCCN1C=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCN1C=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.4 g (5.67 mmol) of [N-(tert-butoxycarbonyl)-glycyl]-sarcosine, which is a known substance (Helvetica Chimica Acta, 1991, 74, 197), 1.3 g (2.84 mmol) of (9S)-9-ethyl-9-hydroxy-1-pentyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione, 2.2 g (11.34 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, and 1.4 g (11.34 mmol) of 4-dimethylaminopyridine were dissolved in methylene chloride (50 mL), and then stirred at room temperature for 1.5 hours.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4].[CH3:27]I.Cl>CN(C)C=O>[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:27])[CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C=O)cc23)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C=O)cc23)c(OC)c1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Sodium hydride (1.23 g of a 60% dispersion in mineral oil) was added to dry N,N-dimethylformamide (100 ml), under an atmosphere of nitrogen. The mixture was cooled in an ice-bath, a solution of methyl 4-(5-formylindol-3-ylmethyl)-3-methoxybenzoate (9.0 g) in N,N-dimethylformamide (20 ml) added slowly, and the mixture stirred for 1 hr. Methyl iodide (4.34 g) was added slowly, stirring continued for 2.5 hr., then the mixture carefully acidified with hydrochloric acid (100 ml) to give an off-white precipitate which was purified by flash chromatography, eluting with 45:50:5 hexane:methylene chloride:ethyl acetate, to give a yellow oil which was crystallized from a mixture of ethyl acetate and hexane to give methyl 4-(5-formyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (7.6 g, 81%) as an off-white powder: mp 116°-118° C.; partial NMR(250 MHz, DMSO-d6): 3.80 (s, 3H, OCH3), 3.83(s, 3H, NCH3), 3.93(s, 3H, OCH3), 4.11(s, 2H, ArCH2Ar'), 8.12(s, 1H, H4 -indole), 9.96 (s, 1H, CHO).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4 mL (0.05 mole) of 40% aqueous monomethylamine. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration (4.6 g). The crude product was recrystallized from acetonitrile yielding 3.4 g (72.7%) of coarse white powder, mp 140°-141° C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:9].[C:21]1([C@H:31]([N:33]([CH2:41][C@@H:42]2[C@@H:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:45][NH:44][CH2:43]2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:36]([O:35][C:34]([N:33]([CH2:41][C@@H:42]1[C@@H:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:45][N:44]([C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH2:43]1)[C@@H:31]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)[CH3:32])=[O:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1

Procedure:
A 0.06 ml portion of pyridine and 103 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) were added in that order to a THF (5.0 ml) solution of 173 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and stirred for 1 week. Thereafter, its work-up and purification were carried out in the standard method to obtain 4-(methoxycarbonyl)phenyl (3R,4S)-3-({(tert-butoxycarbonyl) [(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a crude product. FP: 609.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1>CN(C=O)C.O.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>[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38]([C:16]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=2[C:6]2[C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:39]=1
Reactant: CC1(C)OB(c2cc(C(F)F)ccc2F)OC1(C)C
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
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: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 89.7 %

Procedure:
To a stirred solution of 66.6I (1.1209 g, 2.962 mmol) in dry DMF (10 mL) at 23° C. was added potassium carbonate (1.2262 g, 8.872 mmol) and then tetrakis(triphenylphosphine)palladium (0.3408 g, 0.2949 mmol). The mixture was purged with argon and placed under vacuum and the purging and vacuum process repeated three times. Before heating, 66.50A (1.6019 g, 5.888 mmol) was added via syringe and then the mixture was heated to 90° C. After 19 hours, LC-MS showed that the reaction was complete. The mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to afford 66.50B as a clear oil (994.4 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, dd, J=8.0, 1.8 Hz), 7.94 (1H, d, J=1.6 Hz), 7.50 (3H, m), 7.16 (1H, t, J=9.0 Hz), 6.63 (1H, t), 5.53 (1H, s), 3.96 (3H, s), 2.25 (2H, td, J=7.0, 2.3 Hz), 1.65 (2H, t, J=7.0 Hz), 0.85 (6H, s).
Reaction SMILES: C(=O)(OCC(F)(F)C(F)(F)F)OCC(F)(F)C(F)(F)F.FC(F)(C(F)(F)F)C[NH:24][C:25](=[O:47])[O:26][CH2:27][CH:28]1[CH:33]=[CH:32][CH2:31][CH:30]([CH2:34][O:35][C:36](=[O:46])[NH:37]CC(F)(F)C(F)(F)F)[CH2:29]1>>[C:36](=[O:46])([O:35][CH2:34][CH:30]1[CH:31]=[CH:32][CH2:33][CH:28]([CH2:27][O:26][C:25](=[O:47])[NH2:24])[CH2:29]1)[NH2:37]
Reactant: O=C(NCC(F)(F)C(F)(F)F)OCC1C=CCC(COC(=O)NCC(F)(F)C(F)(F)F)C1
Agent: O=C(OCC(F)(F)C(F)(F)F)OCC(F)(F)C(F)(F)F
Product: NC(=O)OCC1C=CCC(COC(N)=O)C1
Yield: 95.5 %

Procedure:
The reaction was carried out in the same manner as Example 7 except for using 53.5 g (0.1642 mol) of bis(2,2,3,3,3-pentafluoropropyl) carbonate (to be referred to as “BPFC” hereinafter) synthesized in the above Synthesis Example 3 in place of BTFC, and it was confirmed that tetrahydro-m-xylylene bis(2,2,3,3,3-pentafluoropropyl carbamate) (to be referred to as H-XDC-3 hereinafter) was generated as the main product (H-XDA base yield 95.5%). Structural assignment of the product H-XDC-3 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of H-XDC-3, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Cl.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1.C1CCCCC1>CN(C=O)C>[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C:3]2=[O:9])=[CH:13][CH:12]=1
Reactant: ClCc1ccncc1
Reactant: O=C1CCC(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccncc1
Reaction time: 48 h

Procedure:
A suspension of sodium hydride (17.6 g, 0.44 mol) in DMF (500 mL) was stirred with ice bath cooling as succinimide (29.73 g, 0.3 mol) was cautiously added. 4-Picolyl chloride hydrochloride (32.81 g, 0.2 mol) was then added cautiously with vigorous stirring. The mixture was stirred at room temperature for 1 day and then at 100° C. for 2 days. The mixture was then cooled and filtered. The filtrate was concentrated in vacuo to give a black oil. This dark crude product was stirred four times with boiling cyclohexane (150 mL), each time decanting the boiling cyclohexane from the dark residue. Upon cooling the cyclohexane extracts, the desired product crystallized as colorless needles (23.05 g, 60.9%) which were filtered and air dried.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[O:9][N:8]=2)[NH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[O:9][N:8]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1n[nH]c(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a mixture of 3-(5-methyl-2H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)isoxazole (Example 96, Step 4, 400 mg, 1.3 mmol) and K2CO3 (445 mg, 3.3 mmol) in DMF (5 mL) was added 2-chloro-4-(chloromethyl)pyridine (210 mg, 1.3 mmol). The mixture was stirred at RT for 2 h, then diluted with H2O (30 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with H2O (20 mL) and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (Petroleum ether:EA=1:3) to give the title compound as a light yellow solid (300 mg, 53.3%). MS (ES+) C19H13ClF3N5O2 requires: 435. found: 436 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 80 °C
Yield: 96.3 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-[3-(phenylmethoxy)phenyl]acetamide (4.5 g, 0.012 mol) in THF (20 ml) on ice was added the borane-tetrahydrofuran complex (15 ml, 0.023 mol). The reaction was allowed to reflux at 80° C. for six hours. The reduction reaction was placed on ice, acidified using 4 N HCl, then stirred for twenty minutes. The reaction was then basified with an aqueous solution of potassium hydroxide. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (4.3 g, 99% yield): ES−MS (m/z) 372 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1.[C:23]([O:26][CH2:27]Br)(=[O:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([O:26][CH2:27][N:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCBr
Reactant: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3cn(COC(C)=O)cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
1-(1H-Imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol (100 mg) was dissolved in THF (6 ml), and to the solution were added bromomethyl acetate (160 mg) and triethylamine (40 mg). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (eluent, dichloromethane-methanol=20:1) to give the titled compound (30 mg) as a colorless solid.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=CN=1.Cl>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:23]=[CH:24][CH:25]=[CH:20][N:19]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Reactant: Nc1ccccn1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CNc1ccccn1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
10 g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.3 g (118 mmol) of 2-aminopyridine were dissolved in 200 ml of isopropanol at 40° C. The solution was admixed with 3.96 ml (48 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 30 min. The suspension was cooled to 10° C. and the crystallized product was filtered off.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH3:43].O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25][CH2:42][CH3:43])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
6-(Benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (510 mg, 1.082 mmol) was dissolved in DMF (2163 μl). Then potassium carbonate (149 mg, 1.082 mmol) was added followed by iodoethane (96 μl, 1.190 mmol). After stirring at rt for 1 d, water was added. A gummy solid was collected with an aid of water, and dried. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide 6-(benzylthio)-1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)quinolin-2(1 H)-one (534 mg, 99% yield) as white solid. Ink (ESI) [M+H]+=500.0. NMR (400 MHz, DMSO-d6) δ ppm 1.00 (t, J=6.94 Hz, 3 H) 4.01-4.13 (m, 2 H) 4.24 (s, 2 H) 6.60 (d, J=8.80 Hz, 1 H) 6.70 (d, J=9.59 Hz, 1 H) 7.18-7.35 (m, 6 H) 7.38-7.48 (m, 3 H) 7.49-7.63 (m, 3 H) 7.79 (d, J=2.15 Hz, 1 H) 7.96 (d, J=9.59 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5](N)=[C:4]([CH2:11][CH3:12])[CH:3]=1.[I:13]I.C(ON=O)(C)(C)C.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([I:13])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: II
Reactant: CCc1cc(Br)cc(CC)c1N
Agent: CC(C)(C)ON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(Br)cc(CC)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.7 %

Procedure:
A solution of 4-bromo-2,6-diethylaniline (10 g, 44 mmol) in acetonitrile (20 mL) was added dropwise to a solution of I2 (33.4 g, 131.6 mmol), tert-butylnitrite (7.4 mL, 65.8 mmol) in acetonitrile (80 mL), never allowing the internal temperature to exceed 30° C. After stirring 4 h at ambient temperature, Na2SO3 (100 mL, saturated aqueous) was added and stirred for 1 h. The mixture was extracted with hexanes (3×200 mL). The organics were combined, washed with brine, dried over Na2SO4 and concentrated. The crude oil was purified by flash chromatography (100% hexanes) to afford 37A (1.9 g, 13%) as a red oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (t, J=7.45 Hz, 6 H) 2.77 (q, J=7.58 Hz, 4 H) 7.18 (s, 2 H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CS(C)=O>[CH2:21]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCBr
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Cytidine (10 g, 0.041 mol), sodium hydride (2.4 g, 1.5 eq), bromopentane (7.6 ml, 1.5 eq.) in DMSO (90 ml) were reacted as per the procedure of Example 71, Step 1 to yield the 2' and 3' isomers as a foam (7.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[N:8]=[C:7]4[C:6]=3[CH:21]=2)[CH2:28][CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1CCC(S)CC1
Reactant: Brc1ccc2c(c1)-c1nc(-c3ccccn3)cn1CCO2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 140 °C

Procedure:
A mixture of 9-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 3 (200 mg, 0.58 mmol), 1-tert-butylpiperidine-4-thiol (202 mg, 1.69 mmol), Pd2(dba)3 (160 mg, 10 mol %), XantPhos (68 mg, 20 mol %) and DIPEA (410 μL, 2.34 mmol) in dioxane (5 mL) was purged with argon and heated at 140° C. for 1 h using microwave irradiation. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 2-25% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 154 as a white solid (36 mg, 15%). LCMS: RT 2.40 min [M+H]+ 435.1. 1H NMR (CDC3, 400 MHz): δ 8.15-8.14 (1H, m), 7.76 (1H, td, J=8.52, 2.20 Hz), 7.67 (1H, s), 7.33 (1H, dd, J=8.45, 3.89 Hz), 7.15-7.15 (1H, m), 6.96 (1H, d, J=8.43 Hz), 4.46-4.45 (4H, m), 3.03-2.98 (4H, m), 2.20 (2H, t, J=11.00 Hz), 2.06-1.94 (3H, m), 1.66-1.62 (2H, m), 1.06 (9H, s)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.C(NC(C)C)(C)C.[C:42]1([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][N:56]2[CH:60]=[CH:59][C:58]([NH2:61])=[N:57]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:61][C:58]1[CH:59]=[CH:60][N:56]([CH2:55][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[O:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:57]=1)=[O:30]
Reactant: Cc1cnccc1C(=O)O
Reactant: Nc1ccn(Cc2ccccc2Oc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1cnccc1C(=O)Nc1ccn(Cc2ccccc2Oc2ccccc2)n1
Reaction time: 0.17 h

Procedure:
A solution of HATU (38 mg, 0.1 mmol) in N,N-dimethylformamide (0.3 ml) was added to 3-methyl-isonicotinic acid (14 mg, 0.1 mmol, AstaTech Inc) followed by N,N-diisopropylamine (0.050 ml, 0.286 mmol) and left to stand for 10 minutes at ambient temperature. A solution of 1-{[2-(phenyloxy)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 38)(27 mg, 0.101 mmol) in N,N-dimethylformamide (0.1 ml) was then added and the solution left to stand at room temperature overnight. Purification by MDAP (Method D) gave the title compound (20.2 mg); LCMS: (System 1) MH+=385, tRET=0.93 min.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[CH2:6]([NH:8][CH2:9][CH2:10][OH:11])[CH3:7]>>[CH2:6]([N:8]([CH:2]([CH3:1])[C:3]#[CH:4])[CH2:9][CH2:10][OH:11])[CH3:7]
Reactant: CCNCCO
Reactant: C#CC(C)O
Product: C#CC(C)N(CC)CCO

Procedure:
In analogy to example 37.5 and 37.6, 3-Butyn-2-ol and 2-Ethylaminoethanol were converted to yield 2-[Ethyl-(1-methyl-prop-2-ynyl)-amino]-ethanol as colorless oil, MS: 141 (M).
Reaction SMILES: CN([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)C.[CH3:30][NH:31][NH2:32]>C(O)(=O)C>[CH3:30][N:31]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[CH:26]=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:11][CH:12]=2)=[N:5][CH:4]=[N:32]1
Reactant: CNN
Reactant: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CC(=O)O
Product: Cn1ncnc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 6.7 %

Procedure:
In the same manner as Example 48, employing N-(dimethylaminomethylene)-4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide (1.56 g) from Example 46 in glacial acetic acid (75 ml) and methylhydrazine (0.32 g), the title compound (0.10 g) was obtained as a solid, m.p. 155-158° C.; MS, m/z: 369 (M)+.