Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[C:28]3[Cl:48])=[O:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[C:28]3[Cl:48])([OH:24])[C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[CH2:22]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -43 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (150 mg, 1.81 mmol) was added THF (15 mL) and the colorless homogeneous solution was cooled to −43° C. using a CH3CN—CO2 bath. n-BuLi (2.5M in hexanes, 0.7 mL, 1.75 mmol) was added drop wise via syringe which afforded an opaque mixture. The suspension was stirred at −40° C. for 30 min, then a THF solution of tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (430 mg, 0.8 mmol, in 2 mL THF, Intermediate 66: step b) was introduced at −40° C. The reaction mixture was allowed to warm gradually to room temperature over 45 min and then quenched with NH4Cl solution. The aqueous portion was extracted with EtOAc (3×30 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide an amber gum. Chromatography on silica gel (10% acetone-hexane increasing to 30% acetone) afforded the title compound (170 mg) as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.35 (dd, J=8.7, 2.1 Hz, 1H), 4.35 (s, 2H), 4.20 (t, J=8.8 Hz, 1H), 4.07 (s, 3H), 4.00 (dd, J=9.3, 5.6 Hz, 1H), 3.92 (dd, J=8.9, 5.7 Hz, 1H), 3.67 (s, 3H), 3.62 (t, J=8.8 Hz, 1H), 3.52-3.38 (m, 1H), 1.38 (s, 9H). MS (ESI): mass calcd. for C30H31ClF3N5O4: 618.06, m/z found 619.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH2:29]([O:31][C:32](=[O:45])[CH:33](P(OCC)(OCC)=O)[CH:34]([CH3:36])[CH3:35])[CH3:30].[Li]CCCC>C1COCC1>[CH2:29]([O:31][C:32](=[O:45])[C:33](=[CH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=3)[CH:11]=[C:2]([CH3:1])[C:3]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][CH:21]=1)[CH:34]([CH3:35])[CH3:36])[CH3:30]
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCOC(=O)C(C(C)C)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1)C(C)C

Procedure:
Using the procedure described in Example 31 (Step 3), reaction of 4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-benzaldehyde (8) (0.507 g, 1.38 mmol), 2-(diethoxy-phosphoryl)-3-methyl-butyric acid ethyl ester (1.1 g, 4.13 mmol) and 1.6 M nBuLi (2.8 mL, 4.41 mmol) in dry THF (14 mL) afforded 2 isomeric products (222) as oils. Yield: (222-1) Isomer (1) 0.177 (27%); (222-2) Isomer (2) 0.195 g (30%). Isomer (1): 1H NMR (400 MHz, d-CDCl3): δ 1.20 (d, J=6.9 Hz, 6H), 1.32 (t, J=7.1 Hz, 3H), 2.24 (s, 3H), 3.06-3.10 (m, 1H), 3.94 (s, 3H), 4.20-4.25 (m, 2H), 6.58 (d, J=8.8 Hz, 2H), 7.03-7.07 (m, 3H), 7.12-7.14 (m, 3H), 7.22-7.26 (m, 3H), 7.39 (s, 1H), 7.56 (s, 1H), 7.78 (d, J=9.1 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:11])[C:22]2[CH:23]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=2[F:24])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(F)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2cc(F)ccc2F)CC1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a stirred suspension of 100 g of 1-acetyl-4-piperidine carboxylic acid chloride in 500 ml of 1,4-difluorobenzene was added in aliquots, 211 g of anhydrous aluminum chloride. The mixture was stirred at reflux under nitrogen for 3 hrs and allowed to cool to room temperature. The mixture was poured into ice and extracted twice with ethyl acetate. The extracts were washed with saturated sodium bicarbonate solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of the solvent provided an oil which crystallized on standing. The solid was washed with cyclohexane and dried to provide 73.3 g (52.1%) of 1-acetyl-4-(2,5-difluorobenzoyl)piperidine: mp 82°-87° C. Recrystallization from a mixture of isopropyl alcohol, diisopropyl ether and hexane provided product with mp 93°-95° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:7]=[C:8]2[C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11][O:10][C:9]=12)(=[O:3])[CH3:2].[CH3:33][Mg+].[Br-]>C1COCC1>[CH:22]1([CH2:21][N:20]2[C:16]([C:6]3[CH:7]=[C:8]4[C:13]5([CH2:15][CH2:14]5)[CH2:12][CH2:11][O:10][C:9]4=[C:4]([C:1]([OH:3])([CH3:33])[CH3:2])[CH:5]=3)=[CH:17][C:18]([S:29]([NH2:32])(=[O:30])=[O:31])=[C:19]2[CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C[Mg+]
Reactant: CC(=O)c1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc2c1OCCC21CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)O)c3c(c2)C2(CCO3)CC2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a stirred solution of compound 36 (86 mg, 0.19 mmol) in dry THF (2 mL) was added CH3MgBr (3M, 70 μL, 0.21 mmol) and the mixture was stirred at rt for 2 h, quenched with aq. NH4Cl at 0° C. and extracted with EA. The organic layer was concentrated and purified by CC (PE/EE=4/1) to give compound 37 (21 mg, 24%) as a colorless solid. 1H-NMR (CDCl3+D2O, 400 MHz) δ: 0.67-0.72 (2H, m), 0.88-0.91 (2H, m), 1.01-1.05 (5H, m), 1.36-1.44 (3H, m), 1.60 (9H, m), 1.93-1.95 (2H, t, J=10.4 Hz), 2.52 (3H, s), 3.63-3.65 (2H, d, J=7.2 Hz), 4.43-4.45 (2H, t, J=10.4 Hz), 6.35 (1H, s), 6.49 (1H, s), 6.98 (1H, s). MS Calcd.: 472; MS Found: 473 (M+1)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].[C:34]([NH:41][CH2:42][C:43](O)=[O:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[NH:41][CH2:42][C:43]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][C:11]3[N:12]=[CH:13][C:8]4[CH:7]=[C:6]([C:4](=[O:5])[N:3]([CH3:33])[CH3:2])[N:27]([CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[C:9]=4[N:10]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Agent: Cl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CNC(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1

Procedure:
By repeating procedures described in Example 88, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (150 mg, 0.318 mmol), N—BOC-glycine (56 mg, 0.318 mmol) gave a crude product which is purified by SiO2 chromatography, eluting with 0-7% methanol/dichloromethane to give (2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:3]([C:31]#[N:32])=[C:4]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=2)[C:5]([O:18][CH2:19][CH3:20])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:7]=1.[CH3:33]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[C:31]([C:3]1[C:2]([CH3:33])=[CH:7][C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=1)#[N:32]
Reactant: CB(O)O
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(C)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
To tert-butyl (1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate (60 mg, 0.1 mmol) and methylboronic acid (6.4 mg, 0.11 mmol) in 1,4-dioxane (4 mL) was added sodium carbonate (20 mg, 0.2 mmol) in water (2 mL). The reaction was degassed with N2. Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (4 mg, 0.005 mmol) was added and degassed again with N2. The reaction was heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude product. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give tert-butyl (1-{4-cyano-2-ethoxy-5-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate as a yellow oil (0.030 g, 50%). LCMS calculated for C23H30N3O5S (M+H)+: m/z=460.1. found: 460.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: COc1ccc(COC[C@H](C)NC(C)C)cc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3ccc(OC)cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-isopropyl-N—[(S)-2-(4-methoxy-benzyloxy)-1-methyl-ethyl]-amine as described for example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1I.[CH3:15][Si:16]([C:19]#[C:20][Si](C)(C)C)([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:13][NH:12][S:9]([CH2:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:19]([Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:20]2)(=[O:11])=[O:10]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CNS(=O)(=O)Cc1ccc(N)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)cc2c1
Yield: 72.9 %

Procedure:
4-Amino-3-iodo-N-methyl-benzenemethanesulfonamide (1.63 g, 0.005 mol), bis(trimethylsilyl)acetylene (1.28 g, 0.0075 mol) and tetrakistriphenylphosphine Pd(O) (0.578 g, 0.0005 mol) were dissolved in DME (50 mL) and followed by the addition of saturated aqueous Na2CO3 (5 mL). The mixture was heated at reflux for 48 h. The solvent was removed in vacuo. The residue was dissolved in EtOAc and extracted with brine. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. Silica gel chromatography (10-100% EtOAc gradient in hexane) of the residue afforded the product (4) (1.08 g, 76.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>C(O)COCCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[C:11]=2[CH2:10][CH2:9]1
Reactant: NCCCCO
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: OCCOCCO
Product: Cc1ccccc1N1CCc2c(NCCCCO)nc3c(OCC(F)(F)F)cccc3c21
Yield: 85.5 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in diethylene glycol(10 ml), then hereto was added 4-amino-1-butanol(175 μl, 1.9 mmol), and reacted at the same condition of Step 6 in the Example 30 to obtain 495 mg of desired compound as solid in 87% of yield.
Reaction SMILES: [P:1]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:2]CCCCCCCCCCCCCCCCCC.[C:59]([C:63]1[C:68]([OH:69])=[C:67]([CH3:70])[C:66]([CH2:71]Cl)=[C:65]([CH3:73])[CH:64]=1)([CH3:62])([CH3:61])[CH3:60]>>[C:59]([C:63]1[CH:64]=[C:65]([CH3:73])[C:66]([CH2:71][P:1](=[O:2])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:67]([CH3:70])[C:68]=1[OH:69])([CH3:62])([CH3:61])[CH3:60]
Reactant: CCCCCCCCCCCCCCCCCCOP(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Product: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OCCCCCCCCCCCCCCCCCC

Procedure:
21.7 Grams of trioctadecyl phosphite and 5.75 grams 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol were stirred together as a melt at 110° to 120° for 2 hours and at 120° to 125° for 7 hours. The reaction mixture was dissolved in 100 ml. of toluene and the colorless, slightly turbid solution was successively washed with 3N aqueous hydrochloric acid, water, 2N aqueous sodium carbonate solution and water until the wash waters were neutral. After drying over anhydrous sodium sulfate and filtering free of drying agent, the clear filtrate was concentrated by distillation of the solvent at reduced pressures. The residual oil was topped in the "ASCO 50" Rota-Film Molecular Still at a wall temperature of 210° to 215° and a pressure of 1 to 5 microns. After crystallization from methylethyl ketone, the desired product was obtained as while crystals melting at 70° to 72.5°. (compound 4)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1.[I-].[K+]>C(O)C>[I:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:3][C:4]([CH3:13])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(Cl)c2ccc(I)cc2n1
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Yield: 87 %

Procedure:
A suspension of 2 g of 4-chloro-7-iodo-2-methyl-quinoline (European patent application EP 0497371, CA 143946-47-8) in 20 ml absolute ethanol is treated successively with 1.09 ml pyrrolidine, 0.2 ml pyridine and 50 mg potassium iodide under argon. The resulting mixture is refluxed for 24 h. The solvent is then distilled off. The residue is taken up in 50 ml water and basified to pH 12 with a 2N solution of sodium hydroxyde. The solid is filtered upon precipitation and washed with 20 ml of water and 20 ml of diethylether. The final product is dried under vacuum yielding 1.95 g (87%) of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline as an off-white solid. Mp: 99-102° C. MS (EI): peaks at m/e: 338(M+, 100%), 296 (5%), 183(9%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([F:8])=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:17])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(Br)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a round bottom flask containing tert-butyl 3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL) and TFA (3 mL). The reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo, and the resulting residue was neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous mixture was extracted with EtOAc. Organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS (m/z) 208.0 (MH+); tR=0.80 minute; 1H NMR (400 MHz, DMSO-d6) δ 5.54 (s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH3:13].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:13]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCN1CCCCC1CCc1ccccc1N
Product: CCN1CCCCC1CCc1ccccc1NC(=O)c1ccc(OC)cc1

Procedure:
Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with anisoyl chloride according to the procudure of Example 25 provides 2'-[2-(1-ethyl-2-piperidyl)ethyl]-p-anisanilide, m.p. 136.5°-137.5° C. (corr.), from ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[N:23][N:24]([CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2C(OC(C)(C)C)=O)[CH:25]=1.Cl.O1CCOCC1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1cc(N)cn1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3cnn(C[C@H]4CCCN4)c3)ncc2Cl)[C@H]2C=C[C@@H]1C2
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
(1S,2S,3R,4R)-3-(2,5-Dichloropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (100 mg, 0.334 mmol) and (R)-tert-butyl 2-((4-amino-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate (116 mg, 0.435 mmol) were combined with 2-propanol (2 ml) and 4N HCl in dioxane (0.084 ml, 0.334 mmol) in a sealed tube and the reaction was heated to 85° C. for 4 hours. The reaction mixture was concentrated to dryness, and the residue was treated with trifluoroacetic acid (3 mL). After stirring at room temperature for 30 minutes, the reaction mixture was again concentrated to dryness and the residue was suspended in saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with CH2Cl2 (2×10 mL) and ethyl acetate (2×10 mL). The organic extracts were combined, dried (Na2SO4) filtered, and concentrated. The residue was purified by flash chromotography (Analogix, 4 g column, 15 mL/minutes, 0 to 20% methanol (containing 5% NH4OH)/CH2Cl2 over 25 minutes) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30-1.44 (m, 2H) 1.53-1.81 (m, 3H) 2.11 (d, J=8.82 Hz, 1H) 2.51-2.56 (m, 1H) 2.75-2.85 (m, 3H) 2.86-2.89 (m, 1H) 3.37-3.47 (m, 1H) 3.93-4.01 (m, 2H) 4.12 (t, J=7.12 Hz, 1H) 6.31-6.39 (m, 2H) 7.25 (s, 1H) 7.52 (s, 1H) 7.65-7.83 (m, 3H) 7.89 (s, 1H) 9.10 (s, 1H); MS (ESI(+)) m/e 429 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(NCCCCO)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 4-(4-hydroxy-butylamino)-3-nitro-benzonitrile (10.0 g, 42.5 mmol) in pyridine (100 mL) was cooled to 0° C. under nitrogen. Pivaloyl chloride (5.8 mL, 47 mmol) was dropwise added and the resulting solution allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue stripped with toluene. The residue was suspended in ethyl acetate, filtered, and the filtrated concentrated to give 2,2-dimethyl-propionic acid 4-(4-cyano-2-nitro-phenylamino)-butyl ester (13.3 g, 98%) as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1([C:21]([NH2:23])=[O:22])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=2)[CH2:10]1.CO[C:26](OC)(OC)[CH2:27][CH2:28][CH3:29]>C1(C)C=CC=CC=1>[N+:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:21](=[O:22])[NH:23][C:26]([CH2:27][CH2:28][CH3:29])=[N:8]1)[CH2:17]2)([O-:20])=[O:19]
Reactant: CCCC(OC)(OC)OC
Reactant: NC(=O)C1(N)Cc2ccc([N+](=O)[O-])cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCC1=NC2(Cc3ccc([N+](=O)[O-])cc3C2)C(=O)N1

Procedure:
A solution of (±)-2-amino-5-nitroindane-2-carboxamide, trifluoroacetate salt (described in Intermediate 3, 25.0 mg, 0.075 mmol) and 1,1,1-trimethoxybutane (0.060 mL, 0.373 mmol) in toluene (5 mL) was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound. MS: m/z=274 (M+1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([OH:13])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6]
Reactant: Br[Mg]c1ccccc1
Reactant: C=CC=CCCOc1ccc(C(=O)c2ccc(OCCC=CC=C)cc2)cc1
Solvent: C1CCOC1
Product: C=CC=CCCOc1ccc(C(O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
Compound 29 (5.96 g, 15.91 mmol) was dissolved in anhydrous THF (133 mL) with slight heating. Phenylmagnesium bromide (32 mL of a 1.0 M solution in THF, 32 mmol) was added to the solution and the mixture was stirred at room temperature under argon for 5 hours and evaporated to dryness under vacuum. The residue was redissolved in dichloromethane and washed with a saturated solution of ammonium chloride, followed by water. The organic phase was dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel; hexane/CH2Cl2, 1/9) to yield 4.45 grams (62%) of compound 30 as a yellow oil. 1H NMR (300 MHz, DMSO-d6)δ 2.45-2.56 (m, 4H), 3.98 (t, J=6.6 Hz, 4H), 5.01 (dd, J=1.5, 9.9 Hz, 2H), 5.14 (dd, J=1.5, 16.5 Hz, 2H), 5.73-5.87 (m, 2H), 6.12-6.41 (m, 4H), 6.25 (s, 1H), 6.84 (d, J=6.9 Hz, 4H), 7.06 (d, J=7.8 Hz, 4H), 7.15-7.33 (m, 5H).