Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>O1CCCC1>[F:1][CH:2]([F:13])[C:3]1[C:7]([C:8]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[CH2:18][C:17]2[CH:24]=[CH:25][CH:26]=[C:15]([CH3:14])[CH:16]=2)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1
Reactant: Cc1cccc(CC2CCCN2)c1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(CC2CCCN2C(=O)c2c(C(F)F)nn(C)c2F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
At ambient temperature, a solution of 267 mg (1.25 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 200 mg (1.14 mmol) of 2-(3-methylbenzyl)pyrrolidine and 127 mg (1.25 mmol) of triethylamine in 5 ml of tetra-hydrofurane. The reaction mixture is stirred for 1 hour at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×150 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and filtered over a Chemelut™ cardridge to yield after concentration 350 mg of a beige oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 300 mg (71% yield) of [3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazol-4-yl][2-(3-methylbenzyl)pyrrolidin-1-yl]-methanone as a colourless oil (M+H=352).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc2cc(Br)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nncc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-Bromo-2H-phthalazin-1-one (2.5 g), phosphorous oxychloride (11 mL) and diisopropyl ethyl amine (2 mL) was stirred at RT for 30 min then at 90° C. for 3 h. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate and washed with a saturated solution of NaHCO3, NH4Cl, and brine to afford the desired compound (2.0 g). TLC Rf 0.8 (EA/hexane 2/3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([OH:17])=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1.C(C(CCCC)C([O-])=O)C.[Na+].FC(F)(F)C(O)=O.[NH2:36][C:37]1[S:41][N:40]=[C:39]([C:42](=[N:60][O:61][CH2:62][CH:63]=[CH2:64])[C:43]([NH:45][C@@H:46]2[C:58](=[O:59])[N:48]3[C:49]([C:55]([OH:57])=[O:56])=[C:50]([CH2:53]Cl)[CH2:51][S:52][C@H:47]23)=[O:44])[N:38]=1.C(OCC)(=O)C>CS(C)=O>[NH2:36][C:37]1[S:41][N:40]=[C:39]([C:42](=[N:60][O:61][CH2:62][CH:63]=[CH2:64])[C:43]([NH:45][C@@H:46]2[C:58](=[O:59])[N:48]3[C:49]([C:55]([O-:57])=[O:56])=[C:50]([CH2:53][N+:2]4([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]5[CH:15]=[C:14]([OH:16])[C:13]([OH:17])=[CH:12][N:11]=5)=[O:9])[CH2:4][CH2:3]4)[CH2:51][S:52][C@H:47]23)=[O:44])[N:38]=1
Reactant: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reactant: CN1CCN(C(=O)c2cc(O)c(O)cn2)CC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Reaction time: 4 h
Yield: 34.2 %

Procedure:
To a suspension of 1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)piperazine (800 mg) in dimethyl sulfoxide (8 ml) was added sodium 2-ethylhexanoate (840 mg). The solution was added dropwise to a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (965 mg) in dimethyl sulfoxide (7 ml) at room temperature. After being stirred for 4 hours, the mixture was poured into ethyl acetate (200 ml) and the resulting precipitates were collected by filtration. The precipitates were dissolved in water and then adjusted to pH 3.0 with aqueous sodium bicarbonate. The resulting solution was subjected to column chromatography on Diaion HP-20 using 15% aqueous isopropyl alcohol as an eluent and the objective fraction was 10 lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (380 mg).
Reaction SMILES: Br[CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:20]=[N+:21]=[N-:22].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[N:20]([CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(CBr)O3
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(CN=[N+]=[N-])O3
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The compound obtained in Example 295 (1.49 g, 4.62 mmol) was dissolved in dimethyformamide (20 ml). Sodium azide (1.8 g, 27.69 mmol) was added to the mixture, and stirred at 150° C. for 3 hours. After cooling, ethyl acetate and water were added to the mixture for phase separation. The organic phase was washed with water and saturated aqueous NaCl solution in this order, and dried. The solvent was distilled off under reduced pressure to obtain 1.43 g (assayed quantitatively) of the title compound as crude crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][C:4]1=[O:19])[CH3:2].[CH2:20](Br)[CH3:21].[I-].[Na+].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH2:20][CH3:21])[CH2:5][C:4]1=[O:19])[CH3:2]
Reactant: CCN1C(=O)CNCc2cc(OC)c([N+](=O)[O-])cc21
Reactant: CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC(=O)N(CC)c2cc([N+](=O)[O-])c(OC)cc2C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 1-Ethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.42 g, 0.0016 mol), Ethyl bromide (0.244 mL, 0.00329 mol), Sodium iodide (0.0033 g, 0.000022 mol) and N,N-Diisopropylethylamine (1.14 mL, 0.00654 mol) in N,N-Dimethylformamide (4 mL, 0.05 mol) was stirred at room temperature for 22 hrs. The reaction was evaporated and the residue taken up in DCM/water, separated, washed, dried and evaporated to give 1,4-Diethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one the product as a red oil. (0.44 g, 95%). LCMS (m/e) 294 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.95 (s, 1H), 7.45 (s, 1H), 3.95 (s, 3H), 3.87-81 (q, 2H, J=6.82 Hz), 3.61 (s, 2H), 2.98 (s, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.59-52 (q, 2H, J=7.07 Hz), 1.08-1.00 (quin, 6H, J=7.07 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[OH:31][N:30]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(CC(=O)O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(CC(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from {4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-acetic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.6:1) as a colorless oil, MS (ESI+): m/z=389.19 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH:19][CH2:20][CH3:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:22]1(C2CCCCCCCCCC2)[CH2:32]CCCCC=CCC[CH2:23]1.C(Br)C=C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N:19]([CH2:32][CH:22]=[CH2:23])[CH2:20][CH3:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCNc1ccc2[nH]c3cnc(C(=O)OCC)cc3c2c1
Reactant: C1=CCCCC(C2CCCCCCCCCC2)CCCCC1
Solvent: C=CCBr
Solvent: CCO
Product: C=CCN(CC)c1ccc2[nH]c3cnc(C(=O)OCC)cc3c2c1

Procedure:
93 mg of 6-(N-ethylamino)-beta-carboline-3-carboxylic-acid-ethylester in 8 ml of absolute ethanol is heated together with 49 mg of 1,5-diaza-[5.4.0]bicycloundec-5-ene and 50 mg of allyl bromide under nitrogen for 2 h at 70° C. After evaporation, the substance is distributed in ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried, filtered and concentrated. The residue is chromatographed by means of 80 g of silica gel with methylene-chloride/ethanol (12/1) as the eluant, and, after recrystallizing out of ethyl-acetate/ether, 56 mg of 6-(N-allyl-N-ethylamino)-beta-carboline-3-carboxylic-acid-ethylester is obtained (m.p. 190°-192° C.).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:25]=[CH:24][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[CH:22][CH:21]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=5[F:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, B and C subsequently) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: IC.[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1.[CH2:35](N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][N:29]([CH3:35])[CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: CCN(CC)CC
Reactant: N#CC1(c2cc(-c3cnc(N)c(-c4cc(-c5ccccc5)no4)n3)ccn2)CCCNC1
Solvent: ClC(Cl)Cl
Solvent: CI
Product: CN1CCCC(C#N)(c2cc(-c3cnc(N)c(-c4cc(-c5ccccc5)no4)n3)ccn2)C1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Iodomethane (17.09 mg, 7.496 μL, 0.1204 mmol) w as added to a stirred solution of 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]piperidine-3-carbonitrile (51 mg, 0.1204 mmol) and triethyl amine (30.46 mg, 41.96 μL, 0.3010 mmol) in chloroform (1 mL) and the reaction stirred at ambient temperature for 23 hours. A further portion of iodomethane (213.6 mg, 93.68 μL, 1.505 mmol) was added and the reaction stirred at ambient temperature for a further 5.5 hours. The solvent was removed in vacuo and the residue re-dissolved in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 0%-100% B (solvent A: 10 mM ammonium formate in water; solvent B: 10 mM ammonium formate in 1:1 MeOH:CH3CN) over 14 minutes at 25 mL/min]. The relevant fractions were concentrated in vacuo and partitioned between dichloromethane/saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer extracted with dichloromethane (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was freeze-dried to give 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-1-methyl-piperidine-3-carbonitrile Compound I-37 as a yellow solid (14.1 mg, 27% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.96-1.71 (m, 4H), 2.20 (s, 3H), 2.21-2.19 (m, 1H), 2.68 (br d, 1H), 2.75 (br d, 1H), 3.22-3.20 (m, 1H), 7.21 (br s, 2H), 7.51-7.44 (m, 3H), 7.68 (s, 1H), 7.94-7.91 (m, 2H), 8.00 (dd, 1H), 8.12 (s, 1H), 8.59 (d, 1H) and 8.93 (s, 1H) ppm LC/MS m/z 438.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[O:6][CH2:7][C:8]([OH:10])=O.Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CCN(CC)CC.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[O:6][CH2:7][C:8]([N:18]([O:19][CH3:20])[CH3:17])=[O:10]
Reactant: CNOC
Reactant: COc1ccc(OCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(OCC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
To a mixture of CHCl3 (100 mL) with 2-(3,4-dimethoxyphenoxy)acetic acid (4.244 g), N,O-dimethylhydroxyamine hydrochloride (2.341 g), WSC.HCl (4.984 g) and HOBt.H2O (3.513 g), Et3N (3.62 mL) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated, H2O (400 mL) was added, and the organic layer extracted with AcOEt (500 mL) was washed successively with saturated aqueous sodium dicarbonate (400 mL), water (400 mL) and brine (400 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt) to give the titled compound (4.01 g, pale brown oil.)
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH:40]([CH3:42])[CH3:41])[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH:40]([CH3:41])[CH3:42])[C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:34][CH:35]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (2.92 g, 9.51 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (3.25 g, 9.51 mmol) in DCM (40 mL) and DIEA (5.0 mL, 28.7 mmol) was stirred at room temperature for 10 minutes. HBTU (3.61 g, 9.51 mmol) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (500 mL) and washed with water (6×100 mL) The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by EtOAc-DCM/MeOH (20:1) to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (3.68 g, 69%.) LC/MS (APCI+) m/z 558.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N:10]([O-])=O.[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=1.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:20]2[CH:21]=[C:16]([O:15][CH3:14])[CH:17]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]=2[OH:22])=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(N=Nc2cc(OC)cc(C(C)(C)C)c2O)cc1
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
p-Anisidine (257 g) was dissolved in 514 ml of conc. hydrochloric acid, and under ice-cooling, 1530 ml of an aqueous solution containing 158 g of sodium nitrite was added dropwise to the solution. This mixture was added dropwise under ice-cooling to 3000 ml of an aqueous solution containing 356 g of 4-methoxy-2-tert-butylphenol and 416 g of sodium hydroxide. The resulting mixture was stirred at the same temperature for 15 minutes. Conc. hydrochloric acid (about 400 ml) was added dropwise to the reaction mixture to adjust pH of the mixture to 3, and the precipitated crystals were collected by filtration. The crystals were washed and dried, and recrystallized from a mixed solution of chloroform and ethanol to give 400 g of 2-(4-methoxyphenylazo)-4-methoxy-6-tert-butylphenol (yield: 64%, melting point: 125°-127° C., IR: 1600 cm-1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[N:5][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cncc2ccccc12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2cncc3ccccc23)cc1
Temperature: 0 °C

Procedure:
The title compound from Step A above is dissolved in anhydrous pyridine and cooled to 0° C. with stirring. 4-Toluenesulfonyl chloride is added and the reaction is carried out as described in Preparative Example 60, Step D to give the title compound which may be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.O>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])=[O:19]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CCl
Reaction time: 1.5 h
Yield: 95 %

Procedure:
In 3 l of toluene was dissolved 182 g of 2,6-xylidine, and in 1.5 l of water was dissolved 159 g of sodium carbonate. The two solutions were combined, and 203 g of chloroacetyl chloride was added thereto dropwise over 1.5 hours at an inner temperature of from 20° to 35° C., followed by stirring at that temperature for 1.5 hours. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 282 g (95%) of the titled compound.
Reaction SMILES: [C:1]1([C@H:7](/[N:9]=[CH:10]\[C:11]([O:13][CH3:14])=[O:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(CC(O)=O)(F)F.[CH:23]1[CH2:27][CH:26]=[CH:25][CH:24]=1>FC(F)(F)CO>[C:1]1([C@H:7]([N:9]2[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[C@@H:25]3[CH2:26][C@H:27]2[CH:23]=[CH:24]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=N\[C@H](C)c1ccccc1
Reactant: C1=CCC=C1
Agent: O=C(O)CC(F)(F)F
Solvent: OCC(F)(F)F
Product: COC(=O)[C@@H]1[C@H]2C=C[C@H](C2)N1[C@H](C)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of methyl (2Z)-{[(1R)-1-phenylethyl]imino}acetate obtained in Example 42-1 (238 g) in 2,2,2-trifluoroethanol, was added trifluoromethylacetic acid (95.9 mL) at −10° C. The mixture was then stirred at the same temperature. After 1 hr, cyclopentadiene was added dropwise at −10° C. over 30 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].S(=O)(=O)(O)[O-].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CN1CCOCC1>CN(C=O)C>[C:20]([O:19][C:17]([NH:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[OH:1])=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: NCc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-hydroxy-5-chlorobenzylamine (1.22 g, 4.77 mmol assuming the bisulfate salt), (BOC)2O (1.56 g, 7.16 mmol) and N-methylmorpholine (1.05 ml, 9.54 mmol) in DMF (10 ml) was stirred for 5 h at r.t. The reaction was partitioned between water and ethyl acetate and the organic layer was washed with 5% KHSO4 solution (2 times), sodium hydrogen carbonate solution and brine, dried (Na2SO4) and evaporated in vacuo to a solid. The crude product was recrystallized from ethyl acetate/hexanes (1:5, 12 ml) to give the title compound:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]S(C)(=O)=O.[O:24]=[C:25]1[CH2:34][CH2:33][CH2:32][C:31]2[C:30](O)=[C:29]([CH2:36][CH:37]=[CH2:38])[CH:28]=[CH:27][C:26]1=2.C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:30]1[C:31]2[CH2:32][CH2:33][CH2:34][C:25](=[O:24])[C:26]=2[CH:27]=[CH:28][C:29]=1[CH2:36][CH:37]=[CH2:38]
Reactant: C=CCc1ccc2c(c1O)CCCC2=O
Reactant: COC(=O)/C=C/c1ccccc1OCCCCCOS(C)(=O)=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1OCCCCCOc1ccccc1/C=C/C(=O)OC)CCCC2=O
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 1.37 g (4 mmol) of (E)-3-[2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]phenyl]-2-propenoic acid methyl ester from example 76, 0.81 g (4 mmol) of 5-oxo-2-(2-propenyl)-5,6,7,8-tetrahydro-1-naphthalenol, 0.8 g (5.8 mmol) of anhydrous, granular potassium carbonate, 0.08 mL of TDA-1, and 25 mL of toluene was stirred under reflux for 5.5 hr and at room temperature for 12 hr. After being treated with 0.3 g of additional potassium carbonate, the mixture was stirred and refluxed for a further 24 hr. The mixture was cooled and diluted with ether. The organic phase was washed with water and saturated brine and work-up was completed in the usual manner giving a brown oil. This material was chromatographed on 50 g of silica gel. Elution with 1:1 hexane-ether afforded 1.72 g (96%) of (E)-3-[2-[5-[(5-oxo-2-(2-propenyl)-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]phenyl]-2-propenoic acid methyl ester as a yellow-orange oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](F)=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C.C([OH:36])CCC>>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:2]3[N:3]=[C:4]([NH:12][CH:13]4[CH2:16][CH2:15][CH2:14]4)[C:5]4[C:10](=[O:36])[CH2:9][NH:8][C:6]=4[N:7]=3)[CH:26]=2)[CH:22]=[N:23]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCCCO
Reactant: Fc1c[nH]c2nc(Cl)nc(NC3CCC3)c12
Agent: C[Si](C)(C)Cl
Product: O=C1CNc2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CCC3)c21
Temperature: 116 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-N-cyclobutyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (54 mg, 0.22 mmol), 6-aminoindazole (90 mg, 0.68 mmol) and TMSCl (0.090 mL, 0.71 mmol) in nBuOH (3 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give a sample, which was further purified by preparative TLC using CH2Cl2/MeOH (95/5) as developing solvents to give the titled compound (2 mg). MS 336.1 (M+H)