Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C:16](Cl)(=O)[C:17](Cl)=O.CN(C=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[N:1]1([C:6]2[CH:7]=[C:8]3[C:9](=[CH:10][CH:11]=2)[CH2:12][C:13](=[O:15])[CH2:17][CH2:16]3)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(-n3cnnn3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(1H-tetrazol-1-yl)phenyl]acetic acid (0.50 g, 2.4 mmol) in DCM (10 mL) was added oxalyl chloride (0.37 g, 2.9 mmol) and a drop of DMF. The mixture was allowed to stir at RT for 2 hours. The solvent was removed under reduced pressure, and the residue was redissolved in DCM. The solution was cooled to 0° C. with an ice bath. To this solution was added aluminum chloride (0.98 g, 7.4 mmol) in small portions. Ethylene was then bubbled into the reaction via a long needle for 2 hours. LC showed formation of the desired product. The reaction was poured into ice and extracted with DCM. The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (Hexane/EtOAc). The desired 6-(1H-tetrazol-1-yl)-3,4-dihydronaphthalen-2(1H)-one was collected as a off-white solid. LC-MS (IE, m/z): 215 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:40]([N:43]([CH:47]([CH3:49])[CH3:48])[CH2:44][CH2:45]Cl)([CH3:42])[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:45][CH2:44][N:43]([CH:47]([CH3:49])[CH3:48])[CH:40]([CH3:42])[CH3:41])=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ccnc3oc(-c4ccc(O)cc4)c(-c4ccccc4)c23)CC1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N(CCOc1ccc(-c2oc3nccc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)c3c2-c2ccccc2)cc1)C(C)C
Temperature: 85 °C
Reaction time: 17 h

Procedure:
A resealable tube was charged with 4-{2-[2-(4-hydroxy-phenyl)-3-phenyl-furo[2,3-b]pyridin-4-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester 8a (0.070 g, 0.136 mmol), 2-diisopropylaminoethylchloride hydrochloride 9a (0.029 g, 0.143 mmol), cesium carbonate (0.222 g, 0.680 mmol), and DMF (2.0 mL). The system was purged with argon and the tube was sealed. The mixture stirred at 85° C. for 17 h. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a green oil. This oil was purified via preparative thin layer chromatography (eluting with 95:5:0.5, dichloromethane/methanol, ammonium hydroxide) to afford 4-(2-{2-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 10a as a yellow oil. MS (MH+) 642.4; Calculated 641 for C38H51N5O4.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([OH:9])[C:6]([NH:10][C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][N:4]=1)=[O:2].[O-:26]Cl=O.[Na+].[OH-].[K+]>CC(O)(C)C.O>[C:19]1([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([NH:10][C:6]2[C:7]([OH:9])=[N:8][C:3]([C:1]([OH:26])=[O:2])=[N:4][CH:5]=2)=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Reactant: [O-][Cl+][O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of compound 3-h (1 g, 3.0 mmol) in t-BuOH (20 mL) was added to a solution of NaH2PO4H2O (0.86 g, 2.4 mmol) in H2O (4 mL) and NaClO2 (0.8 g, 9 mmol). After being allowed to stir at room temperature for 3 h, the reaction mixture was added to aq. KOH (2M, 15 mL) and extracted with EA (30 mL). The aqueous layer was adjusted to pH=2 by addition of HCl, and then extracted with EA (30 mL) to afford the crude product, 3-1-a, (300 mg). LC-MS (M+H)+ 350.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][O:6][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A mixture of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (13.2 g, 100 mmol), 4-methyl-benzenesulfonyl chloride (18.1 g, 90 mmol), 4-dimethylamino pyridine (15.9 g, 130 mmol) in dichloromethane was stirred at room temperature for 1 h. Then the mixture was washed by aqueous HCl solution (1 N), brine and dried over Na2SO4. The solvent was removed in vacuum to give title compound (23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:42][C:43]2[CH:44]=[C:45]([CH2:49][NH2:50])[CH:46]=[CH:47][CH:48]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:50][CH2:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:44]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: NCc1cccc(CN2CCCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3cccc(CN4CCCC4)c3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), 1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (28 mg, 0.15 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DCE (2 mL).
Reaction SMILES: Cl.Cl.[Cl:3][CH2:4][CH2:5][N:6]([CH2:14][CH2:15][Cl:16])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.O=C(Cl)[O:19][C:20](Cl)(Cl)[Cl:21]>C1COCC1>[ClH:3].[Cl:3][CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:20]([Cl:21])=[O:19])=[CH:9][CH:8]=1)[CH2:14][CH2:15][Cl:16]
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Cl)Nc1ccc(N(CCCl)CCCl)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (37) (0.306 g, 1.0 mmol) in dry THF (25 mL) was added dropwise a solution of diphosgene (197 mg, 1.2 mmol) in an ice bath with vigorous stirring. After being stirred for 30 min, it formed the known crude p-[(N,N-bis(2-chloroethyl)amino)]phenylcarbamoyl chloride hydrochloride (38). The reaction mixture was then neutralized by adding Et3N (0.5 mL), continuously stirred for 10 min, filtered through a pad of Celite and washed with THF (5 mL). The filtrate and washings were combined and was added dropwise into a solution of 3-(acridin-9-yl)amino-5-hydroxymethylaniline (6, AHMA)18 (0.351 g, 1.0 mmol) in dry DMF (10 mL) containing Et3N (0.5 mL) at 0° C. After being stirred for 18 h, the reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in a mixture of CHCl3/MeOH, mixed with silica gel (5 gm) and evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (2×20 cm) and chromatographed using CHCl3/MeOH (100:5 v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness and residue was recrystalized from CHCl3/MeOH to give 1-[3-(acridin-9-ylamino)-5-hydroxymethylphenyl]-3-{4-[bis(2-chloroethyl)amino]phenyl}urea (15, BO-1037), 205 mg (35%); mp 173-175° C.; 1H NMR (DMSO-d6) δ 3.67 (8H, m, 4×CH2), 4.41 (2H, d, J=6.0 Hz, CH2), 5.14 (1H, t, J=6.0 Hz, exchangeable, OH), 6.37 (1H, s, ArH), 6.68 (2H, d, J=9.1 Hz, 2×ArH,), 6.81 (1H, s, ArH), 7.01 (1H, s, ArH), 7.05-7.19 (1H, m, ArH), 7.24 (2H, d, J=9.1 Hz, 2×ArH), 7.55 (4H, m, 4×ArH) 8.05 (2H, m, 2×ArH), 8.25 (1H, m, ArH) 8.46 (1H, m, ArH), 10.48 (1H, brs, exchangeable, NH). Anal. Calcd. for (C31H29Cl2N5O2): C, 63.81; H, 5.18; N, 12.00. Found: C, 64.07; H, 5.26; N, 11.87.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH2:12][CH3:13].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1ccccc1S
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(=O)c1ccccc1S
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 50 g (0.32 mole) of 2-mercaptobenzoic acid, 30 g (0.5 mole) of n-propanol, 200 ml of benzene and 1.0 g of sulfuric acid (93%) was stirred at reflux in a flask equipped with a condenser and Dean-Stark water separator. After 24 hours at reflux, 6.0 ml of water was collected in the water separator. The mixture was cooled to ambient temperature, washed with 150 ml of 10% sodium carbonate solution, washed with three 150 ml water washes, dried over sodium sulfate, filtered and concentrated using a rotary evaporator. The residual oil was distilled to give n-propyl 2-mercaptobenzoate: 41.5 g (62% yield); bp 103°C/0.5 mm; mol wt 196:
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:22]I>CN(C=O)C>[Si:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:21][CH3:22])([CH3:20])[CH3:19])[N:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(O)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
NaH (285 mg, 7.12 mmol) was added portionwise to a stirred solution of 2-tert-butyldimethylsilyloxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (2.0 g, 7.12 mmol) in DMF (30 mL) at room temperature. After 20 min, methyl iodide (1.33 mL, 21.4 mmol) was added, the mixture was warmed to 50° C. and stirred for 16 h at this temperature. The mixture was poured onto water, extracted with EtOAc (×3), the combined extracts were dried (MgSO4), filtered evaporated and the residue purified by column chromatography (20:1 to 10:1, isohexane:EtOAc) to give the title compound (1.20 g, 57%) as a colorless oil; NMR δH (400 MHz, CDCl3) 7.69-7.65 (1H, m), 7.38-7.34 (2H, m), 4.81 (2H, s), 3.15 (3H, s), 1.53 (6H, s), 0.96 (9H, s), 0.12 (6H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl.[F:10][C:11]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:15][CH2:16][C:11]([F:17])([F:10])[CH2:12][CH2:13]2)=[CH:7][N:6]=1
Reactant: Brc1cnc(Br)cn1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: FC1(F)CCN(c2cnc(Br)cn2)CC1
Yield: 38.2 %

Procedure:
A solution of 2,5-dibromopyrazine (200 mg), 4,4-difluoropiperidine hydrochloride (132 mg) and cesium carbonate (603 mg) in dimethyl sulfoxide (5 mL) was stirred overnight at 90° C. under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (89 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][C:15]=2[CH2:17][S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:9]=1.[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[OH:44].[OH-].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:44][C:38]3[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=3[F:36])=[N:14][C:15]=2[CH2:17][S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[N:9]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CN(C)S(=O)(=O)Cc1nc(S(C)(=O)=O)nc2c1c(-c1ccccc1Cl)nn2COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CN(C)S(=O)(=O)Cc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2COCC[Si](C)(C)C

Procedure:
C-[3-(2-Chloro-phenyl)-6-methylsulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide (398 mg) was treated with 2,4-difluorophenol in the presence of KOH using the procedure of step 6 of Example 4 to afford 287 mg of C-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide. Mass Spec. M+H=610.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[N:10]=[C:11](SC)SC.Cl.Cl.[NH2:18][CH2:19][C@@:20]1([OH:28])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[NH:10][C:11]1[O:28][C@:20]2([CH2:19][N:18]=1)[CH:25]1[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]1)[CH2:21]2
Reactant: CSC(=Nc1nc2cccnc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture of dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (90 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (97 mg, 0.42 mmol) and cesium carbonate (230 mg, 0.71 mmol) in DMF (1 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (84 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (br. s., 1 H) 8.37 (dd, J=4.77, 1.51 Hz, 1 H) 7.82 (dd, J=8.03, 1.51 Hz, 1 H) 7.28 (dd, J=8.03, 4.77 Hz, 1 H) 4.05 (d, J=9.54 Hz, 1 H) 3.70 (d, J=9.54 Hz, 1 H) 3.42 (dd, J=15.06, 1.76 Hz, 1 H) 2.75-3.07 (m, 5 H) 2.14-2.26 (m, 2 H) 1.71-1.84 (m, J=13.99, 9.79, 4.17, 4.17 Hz, 1 H) 1.48-1.68 (m, 2 H). MS (LC/MS) R.T.=0.64; [M+H]+=316.15.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>CCO>[Cl:15][C:16]1[N:21]=[C:20]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:19]([F:23])=[CH:18][N:17]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2F)n[nH]1
Reaction time: 12 h
Yield: 49.7 %

Procedure:
To a solution of 5-methyl-1H-pyrazol-3-amine (612 mg, 6.0 mmol) in absolute EtOH (10 ml) was added triethylamine (1.1 ml) and 2,4-dichloro-5-fluoropyrimidine (1.0 g, 6.0 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound as a solid (679 mg). m/z: 228.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[O:17][C:18]4[C:23]([C:24](=[O:32])[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=[C:10]([C:11]#[C:12][CH2:13][OH:14])[C:3]=12.ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[O:17][C:18]4[C:23]([C:24](=[O:32])[C:25]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[C:3]=12
Reactant: Nc1ncnc2c1c(C#CCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1c(CCCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reaction time: 48 h
Yield: 42 %

Procedure:
To a solution of example 59 (0.170 g, 0.401 mmoles) in methanol (4 ml), palladium on charcoal 1 (10%, 0.050 g) was added and hydrogenated at 5 kg/cm2 for 48 h. The reaction mixture filtered through celite pad and washed with methanol. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.072 g, 42% yield). MP: 182-184° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.11 (s, 1H), 8.05 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (m, 1H), 7.49 (t, J=7.1 Hz, 1H), 7.39-7.20 (m, 8H), 4.62 (t, J=4.6 Hz, 1H), 3.45 (q, J=6.1 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 1.78 (m, 2H). Mass: 427.87 (M+).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH:18]=[O:19])[C:6]([NH:8][C:9]1[S:10][C:11]([O:14][CH3:15])=[N:12][N:13]=1)=[O:7])[CH2:2][CH:3]=[CH2:4].Cl>O>[CH3:15][O:14][C:11]1[S:10][C:9]([N:8]2[CH:18]([OH:19])[CH2:17][CH2:16][N:5]([CH2:1][CH2:2][CH:3]=[CH2:4])[C:6]2=[O:7])=[N:13][N:12]=1
Reactant: C=CCCN(CCC=O)C(=O)Nc1nnc(OC)s1
Agent: Cl
Solvent: O
Product: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O

Procedure:
The diethyl acetal of 3-[1-but-3-enyl-3-(5-methoxy-1,3,4 -thiadiazol-2-yl)ureido] propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflex condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2 -yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3N(C)C(C)=NC=3)O)[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.[CH3:39][C:40]1[C:45]([C:46]([C:48]2[N:52]([CH3:53])[N:51]=[N:50][CH:49]=2)=[O:47])=[CH:44][CH:43]=[C:42]([CH3:54])[N:41]=1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[C:40]([CH3:39])=[N:41][C:42]([CH3:54])=[CH:43][CH:44]=3)([C:48]3[N:52]([CH3:53])[N:51]=[N:50][CH:49]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.68 mL, 1.7 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (0.404 g, 0.936 mmol, Intermediate 45: step d) in dry THF (17 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (0.346 g, 1.601 mmol, Intermediate 19: step b) in dry THF (8 mL) was added dropwise. The reaction was stirred for 10 minutes, then was moved into an ice bath and allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-4% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=1.7 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.76 (dd, J=8.1, 1.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.40 (dd, J=8.8, 2.2 Hz, 1H), 6.96-6.90 (m, 2H), 6.83 (s, 1H), 5.01 (s, 1H), 4.33 (s, 2H), 4.09 (s, 3H), 3.91 (s, 3H), 2.51 (s, 3H), 2.32 (s, 3H); MS m/e 569.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][N:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])=[CH:31][N:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(OCC(F)(F)F)cn1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(OCC(F)(F)F)cn3)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-6-trifluoromethanesulfonyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (370 mg, 0.9 mmol) with 2-aminomethyl-5-(2,2,2-trifluoroethoxy)-pyridine (180 mg, 0.9 mmol) in toluene (8 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain 7-chloro-6-{[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[CH:7]=1.C(O)(C(F)(F)F)=O.[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:17]([N:24]1[CH2:28][C@:3]2([O:2][CH3:1])[C:4](=[O:9])[NH:5][C:6](=[O:8])[C@@H:7]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC1=CC(=O)NC1=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@]12CN(Cc3ccccc3)C[C@H]1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a 0° C. solution of 3-methoxy-1H-pyrrole-2,5-dione ({see M. Couturier, J. L. Tucker, B. M. Andresen, P. Dube, J. T. Negri, Org. Lett., 2001, 3, 465-467}, 950 mg, 7.47 mmol) and TFA (0.070 mL, 0.897 mmol) in DCM (70 mL) was added slowly a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (3.06 mL, 12.0 mmol) in DCM (30 mL) at a rate such to maintain the internal reaction temperature <2° C. The resulting bright yellow solution was slowly warmed to ambient temperature and stirred for 18 hrs. The reaction mixture was then cooled to 0° C. and a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (0.956 mL, 3.74 mmol) in DCM (1 mL) was added dropwise and was warmed to rt and stirred for 3 hrs. The reaction mixture was diluted with saturated sodium bicarbonate (25 mL), the layers were separated and the organic solution was dried (magnesium sulfate), filtered and concentrated under reduced pressure, giving a thick, yellow oil. The crude residue was purified by column chromatography eluting with 5%-50% EtOAc/heptane and again with 0%-25% EtOAc/Heptane to afford the titled compound (1.19 g, 61% yield, 70% purity) as a clear oil that was carried forward to the next step without further purification.