Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[C:9]=2[F:37])=[O:6])[CH2:3][CH2:2]1.CO.C(Cl)Cl.[C:43](OC(=O)C)(=[O:45])[CH3:44]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:43](=[O:45])[CH3:44])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:36])[C:9]=2[F:37])[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1
Solvent: CO
Solvent: ClCCl
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A suspension of compound 25 (100 mg, 0.156 mmol, TFA salt) in acetic anhydride (1 mL) was stirred at RT for 2 days. The reaction mixture was quenched by addition of methanol and water. The fine suspension was collected by filtration, rinsed successively with water, 1N NaOH, water, and air-dried. The crude product was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV, then 10/90 over 5 CV) to afford the title compound 26 (34 mg, 0.06 mmol, 38% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.57-8.44 (m, 3H), 8.38 and 8.34 (2s, 1H), 8.30 and 8.24 (2d, J=8.2 Hz, 1H), 8.04 (bt, J=8.3 Hz, 1H), 7.82-7.75 (m, 1H), 7.32-7.25 (m, 1H), 6.87 (bd, J=2.7 Hz, 1H), 6.79-6.74 (m, 1H), 4.71 and 4.59 (2s, 2H), 3.54-3.40 (m, 4H), 3.24 and 3.21 (2s, 3H), 2.61-2.53 (m, 1H), 2.13 and 2.05 (2s, 3H), 0.73-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 568.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:25]([F:28])([F:27])[F:26])=[C:21]([CH:24]=1)[CH:22]=O.[BH4-].[Na+]>CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:25]([F:26])([F:27])[F:28])=[C:21]([CH:24]=1)[CH2:22][NH:15][C:13]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1ccc(Cl)cc1CNc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Temperature: -20 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and 5-chloro-2-(trifluoromethyl)benzaldehyde (85 mg, 408 μmol) in MeOH (3 ml) was stirred at 45° C. for two days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated. Trituration with hexanes afforded a white solid as desired product (88 mg, 70% yield). MS +m/z: 436 (M+H)+
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27]>C(O)C>[CH2:2]([O:4][N:5]=[C:25]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH2:12][C:11]=1[OH:24])[CH2:26][CH3:27])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 1578.4 %

Procedure:
Ethoxyamine hydrochloride (0.42 g; 4.1 mmole) and then aqueous 1% sodium hydroxide (17.0 ml) were added to a solution of 3-hydroxy-5-(5-indanyl)-2-propionylcyclohex-2-en-one (1 10 g; 3.87 mmole) in anhydrous absolute ethanol (200 ml). The mixture was stirred at room temperature for a period of 4 hours and then the ethanol was removed by evaporation under reduced pressure using a rotary evaporator. The residue was treated with dichloromethane and the organic phase was washed twice with dilute aqueous hydrochloric acid and twice with water. The organic phase was dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5(5-indanyl)-cyclohex-2-en-1-one (1 20 g; 94.8%) as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:20]([C@@H:19]2[NH:18][C@@H:17]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C@:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[C@H:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Br)c2F)c(OC)c1
Yield: 51.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.64 mmol), was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.18 g, 0.99 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield 0.22 g, 51%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]=[CH:23][C:24]#[N:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1.N1C=CC=CC=1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH:22]=[CH:23][C:24]#[N:25])(=[O:21])=[O:20])=[CH:17][CH:18]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1

Procedure:
4.9 grams (0.025 mol) of para-toluenesulfonyl chloride, and 4.5 g (0.025 mol) of 3-(4-aminobenzenesulfonyl) acrylonitrile in chlorofrom are reacted for 48 hours at room temperature in the presence of 2.2 ml (0.027 mol) of pyridine, and the reaction mixture is worked up as in Example 1. The product, recrystallized from ethanol, and having a melting point of 172°-175° C, is 3-[4-(4-methylbenzenesulfonamido)benzenesulfonyl]acrylonitrile: ##SPC13##
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([OH:21])=O)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=O)C1C=CC=CC=1.[NH2:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26]>>[NH2:11][C@@H:12]([CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:19]([NH:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26])=[O:21]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(N[C@@H](Cn1ccnc1)C(=O)O)OCc1ccccc1
Product: N[C@@H](Cn1ccnc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of N-[(benzyloxy)carbonyl]-3-(imidazol-1-yl)-L-alanine and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by catalytic hydrogenation there was obtained (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(imidazol-1-yl)propionamide, MS: 365 (M+H)+, as a colourless foam.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.ClC1C=C(C=CC=1)C(OO)=[O:16].O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:1][C:2]1[NH:3][C:4]2=[N+:5]([O-:16])[CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1
Reactant: Cc1cc2cccnc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2ccc[n+]([O-])c2[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2-methyl-7-azaindole (5 g, 37.8 mmol) in 1,2-dimethoxyethane (40 ml) is added m-chloroperoxybenzoic acid (10.4 g, of a 77% w/w solid, 46.6 mmol). The reaction mixture is stirred at 0° C. for 30 minutes, at room temperature for 3 hours and then poured into water (400 ml). The solution is basified to pH 9-10 using saturated potassium carbonate solution. The aqueous is extracted with DCM (2×100 ml) and the organic portions are combined, dried (MgS04) and concentrated in vacuo. Purification of the resulting crude by chromatography on silica eluting firstly with neat ethyl acetate followed by DCM/MeOH (10:1) yields the titled compound as a yellow powder. (MH+297 appears as a dimer)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:20][C:10]3[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:12][CH:13]=[C:8]([N:6]4[CH2:5][CH2:4][O:3][C@@H:2]([CH3:1])[CH2:7]4)[CH:9]=3)=[C:23]([CH3:39])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: C[C@H]1CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCO[C@@H](C)C2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using (S)-5-(2-methylmorpholino)-2-morpholinopyridin-3-amine (85 mg, 0.305 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (83 mg, 0.305 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (80 μL, 0.31 mmol), and NMP (350 μL, 3.7 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded 7-fluoro-3-methyl-N-(5-((2S)-2-methyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine as a yellow solid (absolute configuration of stereocenter not determined) 1H NMR (500 MHz, chloroform-d) δ ppm 8.70-8.76 (1H, m), 7.85-7.94 (2H, m), 7.75-7.85 (2H, m), 7.59 (1H, d, J=2.7 Hz), 7.39 (1H, ddd, J=7.1, 5.0, 1.6 Hz), 7.25-7.33 (1H, m), 6.77 (1H, s), 6.23 (1H, d, J=2.7 Hz), 3.84-3.99 (5H, m), 3.56-3.71 (2H, m), 3.23 (4H, br. s.), 3.15 (1H, dt, J=11.7, 2.2 Hz), 3.02-3.11 (1H, m), 2.63-2.74 (1H, m), 2.31-2.43 (4H, m), 1.16 (3H, d, J=6.4 Hz). Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[CH3:17][O:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)([O-:21])(=[O:20])=[O:18].[CH3:16][N:2]([CH3:1])[S:3]([C:6]1[CH:15]=[CH:14][C:9]2[N+:10]([CH3:17])=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2ccc(S(=O)(=O)N(C)C)cc2s1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1sc2cc(S(=O)(=O)N(C)C)ccc2[n+]1C
Temperature: 130 °C
Yield: 84 %

Procedure:
A mixture of Compound 24 (2.0 g, 7.8 mmol) and p-toluenesulfonic acid methyl ester (2.2 g, 11.7 mmol) was heated in a pressure tube at 130° C. for 2 hours. The mixture was allowed to cool to room temperature, and the resulting mass was triturated with ethyl acetate (25 ml) until an off-white solid separated. The solid was collected by centrifugation, washed with ethyl acetate and dried under vacuum to yield 2.9 g (84%) of Compound 25 whose structure is given below:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>ClCCl.CO.[Pd]>[CH3:41][S:38]([CH2:37][CH2:36][NH:35][CH2:33][C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)[C:27]=3[CH:26]=2)=[CH:29][CH:30]=1)(=[O:40])=[O:39]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5 g, 10.6 mmoL) in dichloromethane (50 mL) was charged with a solution of 2-aminoethylmethylsulfone (3.2 g, 11.7 mmoL) in methanol (25 mL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion and then was charged with 5% Pd—C (750 mg) and stirred under a hydrogen atmosphere using balloon pressure for 12-16 hours until reaction completion. The obtained mixture was filtered through Celite® pad and rinsed with methanol (5 mL) and dichloromethane (15 mL) mixture. The filtrate was distilled to low volume and the obtained solution was charged with methanol (25 mL). The reaction mixture was stirred for 2-6 hours and the yellow solid which precipitated out was filtered and washed with methanol (10 mL). The solid obtained was dried under vacuum at 40-45° C. to furnish Lapatinib freebase (5 g, Yield=85%, HPLC purity>99%).
Reaction SMILES: [NH:1]1[C:6]2N=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.[CH2:22](Br)CCC>>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[C:6]2[CH2:22][CH2:8][CH2:9][CH2:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12]
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: BrCc1cccc(Br)c1
Reactant: CCCCBr
Product: O=c1oc(=O)n(Cc2cccc(Br)c2)c2c1CCCC2

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting the product of Example 113A for the product of Example 1A and substituting 3-bromobenzyl bromide for n-butyl bromide (0.049 g, 46%). MS (ESI−) m/z 334 (M−H)+.
Reaction SMILES: F[C@@H:2]1[CH2:6][N:5]([C:7](OC(C)(C)C)=O)[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1.Br[C:37]1C=C(C(F)(F)F)C=CN=1>>[CH3:7][NH:5][C@H:4]([C:14]([NH:15][C@@H:16]1[C@@H:23]2[C@@H:19]([CH2:20][N:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=3)[CH2:22]2)[CH2:18][CH2:17]1)=[O:24])[CH2:3][CH:2]([CH3:6])[CH3:37]
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1nccc(Cl)n1
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccnc(C(F)(F)F)n3)C[C@@H]21

Procedure:
The title compound was prepared by substituting tert-butyl methyl((S)-4-methyl-1-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino)-1-oxopentan-2-yl)carbamate from Example 619 Step 1 for (2S,4S)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate and 4-chloro-2-(trifluoromethyl)pyrimidine for 2-bromo-4-(trifluoromethyl)pyridine in the procedure described in Example 637: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.23 (d, J=6.1, 1H), 7.73 (dd, J=6.7, 4.2, 1H), 6.34 (d, J=6.1, 1H), 4.25 (dt, J=14.3, 7.2, 1H), 3.73-3.52 (m, 3H), 3.28 (dd, J=11.2, 4.0, 1H), 3.15 (dd, J=7.9, 5.8, 1H), 2.83-2.65 (m, 2H), 2.39 (d, J=0.5, 3H), 2.13 (td, J=12.5, 7.3, 1H), 2.01-1.90 (m, 1H), 1.93-1.67 (br m, 1H), 1.85 (td, J=13.4, 6.6, 1H), 1.74-1.60 (m, 2H), 1.52 (ddd, J=14.0, 7.9, 6.3, 1H), 1.41 (td, J=13.3, 7.9, 1H), 0.93 (d, J=6.6, 3H), 0.89 (d, J=6.6, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2[nH]ccc12

Procedure:
A round-bottom flask was charged with 4-nitroindole (4.8 g, 30 mmol), Palladium on carbon (10%, 480 mg), and THF (50 mL), and the mixture was stirred under one hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was filtered off and the filtrate was concentrated to afford 4-amino-1H-indole, which was used directly in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[CH3:15][N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=O)[CH2:20]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:19]2[CH2:20][CH:21]3[N:16]([CH3:15])[CH:17]([CH2:23][CH2:22]3)[CH2:18]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: COC(Cc1cc(Br)ccc1N)OC
Reactant: CN1C2CCC1CC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(Cc1cc(Br)ccc1NC1CC2CCC(C1)N2C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.1 %

Procedure:
Crude compound 67 (225.4 mg, 0.866 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (241.1 mg, 1.732 mmol) were stirred in acetic acid (10 mL) under argon in the presence of anhydrous sodium sulfate (1.230 g, 8.660 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (550.6 mg, 2.598 mmol) was then added and the mixture stirred for 24 hours at room temperature. After dilution with a mixture of 8:1 ethyl acetate:Hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95%) to yield a pale yellow residue, 83 (120 mg, 36.1%) as an 5:1 or 1:5 mixture of endo/exo stereoisomers. 1H NMR (major isomer-DMSO-d6) δ 1.56-1.70 (m, 2H), 1.87-1.99 (m, 4H), 2.04-2.09 (m, 2H), 2.21 (s, 3H), 2.79 (d, 2H, J=5.3 Hz), 3.03-3.17 (m, 2H), 3.28 (s, 6H), 3.40-3.49 (m, 1H), 4.54 (t, 1H, J=5.3 Hz), 4.98 (s, 1H), 6.36 (d, 1H, J=9.3 Hz), 7.11-7.21 (m, 2H); ESI-MS (m/z, %): 383/385 (MH+, 100%).
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[O:8][C:7](=[O:17])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCCC1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:5]([CH2:4][NH:2][CH3:1])=[CH:6][C:7](=[O:17])[O:8]2)=[CH:13][CH:12]=1
Reactant: CN
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1cc(=O)oc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methylamine in tetrahydrofuran (2M, 1.10 ml) was added to an ice-cooled mixture of 4-bromomethyl-7-methoxycoumarin (0.30 g), potassium carbonate (0.5 g) and dichloromethane (10 ml). The mixture was stirred at room temperature for 2 days then added to an aqueous solution of potassium carbonate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (eluent 10% methanol in dichloromethane), then crystallised from methanol to give the title compound as a white solid (0.14 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11](Cl)=[O:12])[S:7][C:6]=2[CH:14]=1.[CH3:15][OH:16].Cl[Si](C)(C)C.II>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]([O:16][CH3:15])=[O:12])[S:7][C:6]=2[CH:14]=1
Reactant: Cc1ccc2c(Cl)c(C(=O)Cl)sc2c1
Reactant: CO
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1sc2cc(C)ccc2c1Cl
Reaction time: 24 h

Procedure:
Crude 6-methyl-3-chlorobenzo[b]thiophene-2-carbonyl chloride (5 g, 20.46 mmoles) was transferred to a 250 ml round bottomed flask. Anhydrous methanol (Aldrich, 80 ml) was added and the acid chloride dissolved by stirring. To this stirred solution was added chlorotrimethylsilane (3.0 equivalents, 61.38 mmole, 6.68 g, 7.80 ml). The reaction mixture was stirred at room temperature and the progress of the reaction monitored by TLC (silica, 1:1 hexane:ethyl acetate, iodine and UV visualization). The reaction was shown to be complete after 24 hours. The resulting slurry was concentrated in vacuo to give 4.80 g of a yellow solid, which was shown by 1H NMR (DMSO-d6, 400 MHz) to be the desired material. The crude methyl ester was shown to be pure and used directly.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:9]2[CH:19]=[CH:20][CH:21]=[C:8]2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([O-:27])=[O:26].[Na+]>>[CH2:13]([N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])=[C:7]([OH:22])[C:8]2=[CH:21][CH:20]=[CH:19][N:9]12)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2cccn21
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: CCCCCCn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cccn21

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-hexyl-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 336 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[C:33]([O-])(=[O:35])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:17]1[CH:18]=[CH:19][C:20]([CH:33]=[O:35])=[CH:21][CH:22]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCCCCCCN(CCCCCCOC(C)=O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCCCCCN(CCCCCCOC(C)=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
N,N-Dimethylformamide (DMF, 250 mL) was added dropwise with stirring under nitrogen to phosphorous oxychloride (115 g, 0.751 mol) at 0° C. The resulting orange solution was stirred for 2 hours, then a solution of 236 g (0.626 mol) of N,N-di-(6-acetoxyhexyl)aniline (A2) in 250 mL of DMF was added slowly. The reaction mixture was stirred under nitrogen for 1 hour at 0° C. and then for 6 hours at 80° C. After cooling, the solution was poured onto 500 g of ice plus 200 g of sodium acetate, and the resulting mixture was extracted with dichloromethane (4×250 mL). The combined organic extracts were washed four times with 250 mL portions of water, dried over anhydrous sodium sulfate, and then concentrated at reduced pressure to produce a light brown oil. The oil was fractionally distilled in vacuo to yield 192 g (76%) of A3 as a gold oil, bp 220°-260° C. (0.007 mm).