Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:21])=O.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO.C(Cl)(Cl)Cl>[CH:19]([N:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:13]1)([CH3:21])[CH3:18]
Reactant: c1ccc2c(c1)CCCC2N1CCCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCCN(C2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
A 100 ml 3-necked flask under nitrogen atmosphere was charged sequentially with N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (0.73 g; 3.2 mmol) in THF (20 ml), methanol (10 ml) and acetone (3.3 ml; 45 mmol). To this stirred solution, sodium cyanoborohydride (0.30 g; 4.75 mmol) was added as a solid followed by acetic acid (0.24 ml; 4.2 mmol). After stirring at ambient temperature for 45 minutes, tlc analysis (silica gel, 9:1 CHCl3:CH3OH) of an aliquot revealed the absence of starting amine (Rf 0.03) and the presence of a major component with Rf 0.16. The content of the flask was then concentrated in vacuo. The residue was treated with aqueous sodium bicarbonate and extracted several times with ethyl acetate which was then dried with sodium sulphate. Filtration and removal of solvent in vacuo gave an oil which was subjected to high vacuum for four hours at ambient temperature to yield the title compound (0.87 g); tlc (ibid), homogeneous, Rf 0.16; 1H nmr δ 1.01-1.05 (6H), 3.88-3.92 (m, 1H), 6.98-7.22 (m, 3H), 7.77-7.79 (1, H). Anal: Calcd. for C18H28N2; C, 79.36; H, 10.36; N, 10.28. Found: C, 79.46; H, 10.12; N, 10.08.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[C:18]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C:22]1[CH:27]=[C:26]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1cc(I)ccc1OCc1ccccc1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: CC(=O)Oc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1OCc1ccccc1

Procedure:
This compound was obtained by coupling rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 5-iodo-2-(phenylmethoxy)phenyl acetate under the conditions described in Example 26. The crude product was chromatographed over the 50 fold amount of silica gel using methylene chloride. The combined fractions were evaporated and the residue was crystallized from methanol after treatment with charcoal and was recrystallized from ether/ hexane for analysis to give colorless crystals with m.p. 117°-120°.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(Cl)cc21
Reaction time: 6 h
Yield: 60.4 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 273 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3.11 g, 2.1 mL, 27.3 mmol) at 20° C. After 6 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (5 mL) and ethylenediamine (1.23 g, 1.38 mL, 20.5 mmol) added. The mixture was stirred for 15 h, then concentrated in vacuo. The residue was triturated with water and the solid obtained by filtration. Purification by chromatography (silica, 25 g pre-packed SiliCycle cartridge, 0-5% methanol in dichloromethane gradient increasing over 15 min) gave N-tert-butyl-2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (63 mg, 165 μmol, 60%) as a pale yellow powder. MS (M+Na)+=405; 1H NMR (CDCl3) δ: 11.84 (br. s., 1H), 9.05 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.14 (d, J=3.4 Hz, 1H), 7.96 (s, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.08 (dd, J=8.5, 1.7 Hz, 1H), 4.04 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[C:16]([C:6]2[S:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
1-(5-(3-(Trifluoromethyl)phenyl)thien-2-yl)ethanone is prepared from 2-acetyl-5-bromothiophene acid and 3-trifluoromethylbenzeneboronic acid according to general procedure A.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Br)[N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: OB(O)Oc1ccccc1
Reactant: CC(=O)Nc1cc(N)c(C#N)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cc(N)c(C#N)c(-c2ccccc2)n1
Temperature: 130 °C
Yield: 72.7 %

Procedure:
A mixture of bromide from Example 65A (45 mg, 0.18 mmol), Na2CO3 (38 mg, 0.35 mmol), and Pd(PPh3)4 (10 mg, 0.009 mmol) was stirred in DMF/THF/H2O (1:1:0.5) under nitrogen in a microwave reactor vial. Phenyl boric acid (26 mg, 0.21 mmol) was added. The resulting mixture was capped and heated at 130° C. for 20 min in a microwave reactor. The crude mixture was partitioned between EtOAc and water. The organic layer washed with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The crude residue was purified by a Gilson reverse phase HPLC to provide the titled compound (33 mg, 72% yield). 1H NMR (300 MHz, d6-DMSO) δ 10.44 (s, 1H), 7.74-7.68 (m, 2H), 7.55 (s, 1H), 7.52-7.46 (m, 3H), 6.98 (s, 2H), 2.08 (s, 3H). MS (ESI) m/e 253 (M+H)+; m/e 251 (M−H)−.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]5[CH:31]=[CH:30][C:29]([CH:32]6[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]6)=[CH:28][CH:27]=5)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Reactant: Nc1ccc(C2CCN(CCO)CC2)cc1
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CCO)CC5)cc4)nn23)c1)N1CCCC1
Yield: 25 %

Procedure:
The compound was prepared in an analogous fashion to Example 522 using 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 2-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanol to provide 2-[4-(4-{7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}phenyl)-piperidin-1-yl]ethanol as a brown lyophilate (49.2 mg, 25% yield). LCMS (E/I+) 547 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.22 (broad s, 1H), 9.04 (s, 1H), 8.53 (s, 1H), 8.42 (d, 1H, J=7.6 Hz), 7.82 (m, 2H), 7.70 (d, 2H, J=8.5 Hz), 7.29 (d, 1H, J=4.7 Hz), 7.22 (d, 2H, J=8.4 Hz), 7.00 (d, 1H, J=4.7 Hz), 3.77 (t, 2H, J=5 Hz), 3.42 (d, 2H, J=11.9 Hz), 3.37 (m, 1H), 3.18 (m, 6H), 3.09 (m, 2H), 2.75 (m, 1H), 1.95 (m, 3H), 1.65 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:13]=[CH2:14])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Cl[C:17](Cl)(Cl)[C:18](Cl)=[O:19].P(Cl)(Cl)(Cl)=O>CCOCC.COCCOC.C(O)(=O)C.O.[Cu].[Zn].[Zn]>[C:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([CH:13]2[CH2:17][C:18](=[O:19])[CH2:14]2)[C:3]([CH3:15])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: C=Cc1c(C)c(Cl)cc(C(C)=O)c1OC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: COCCOC
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C1CC(=O)C1
Temperature: 40 °C
Yield: 26.6 %

Procedure:
To a solution of 1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone (530 mg, 2.4 mmol) in ether (10 mL) was added zinc-copper couple (1.8 g, 14 mmol). The reaction mixture was heated at 40° C. and a solution of trichloroacetyl chloride (1.4 mL, 13 mmol) and phosphoryl chloride (1.2 mL, 13 mmol) in 1,2-dimethoxyethane (3 mL) was added slowly over 2 h. After addition, the reaction mixture was stirred under reflux overnight. The reaction was quenched with saturated NaHCO3 solution and diluted with ether. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue and zinc (0.31 g, 4.7 mmol) in acetic acid (10 mL) was stirred at room temperature for 2 h and then reflux overnight. Another portion of zinc was added and reflux for another 4 h. The mixture was diluted with water and extracted with ether. The organic phase was washed successively with a saturated NaHCO3 solution, water and brine, then dried over MgSO4 and concentrated. The crude material was purified with flash chromatography (eluting with 0 to 30% ethyl acetate in hexanes) to give the desired product (0.17 g, 27%). LCMS calculated for C14H16ClO3 (M+H)+: m/z=267.1; Found:267.0
Reaction SMILES: [F:1][C:2]1[C:3]2[N:11]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]4)[CH:14]=[C:13]3[F:22])[CH:10]=[N:9][C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[C:3]2[N:11]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:20])([CH3:21])[O:18]4)[CH2:14][CH:13]3[F:22])[CH:10]=[N:9][C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)C(F)=C[C@H]2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)C(F)C[C@H]2O1

Procedure:
7-fluoro-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta [d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (5-9) (70 mg, 0.23 mmol, 1 equiv) was dissolved in MeOH (5 mL), the system was placed under nitrogen and 10% Pd/C (25 mg, 0.23 mmol, 1 equiv) was carefully added. The resulting mixture was stirred under a H2 atmosphere (1 atm) until disappearance of the starting material. Hydrogen was removed followed by filtration through a celite plug and washing of the solids with MeOH (4×20 mL). The filtrate was concentrated and the residue was purified via reverse phase chromatography (0-50% CH3CN in water with 0.1% TFA modifier) to afford 7-fluoro-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (5-12) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.78 (d, J=3.5 Hz, 1H); 7.73 (s, 1H); 5.20-5.38 (m, 1H); 5.07 (s, 1H); 4.92 (m, 1H); 4.82 (s, 1H); 2.72-2.78 (m, 1H); 2.26-2.37 (m, 1H); 1.61 (s, 3H); 1.32 (s, 3H). LRMS m/z (M+H) 311.0 found, 311.1 required.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:47][C@H:48]([C:56]([O:58][CH2:59][C:60]#[N:61])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:47][C@H:48]([C:56]([O:58][CH2:59][C:60]#[N:61])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: N#CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N#CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Yield: 62 %

Procedure:
300 mg (0.69 mmole) of Z-Tyr-Gly-Gly-OH was dissolved in 5 mL dry THR, and the temperature was lowered to -10° C. in a dry ice/ethylene glycol bath. One equivalent of N-methyl morpholine and 1 equivalent of isobutyl chloroformate was added with stirring. One equivalent of H-L-Phe-OCH2CN, HCl (166 mg), and 1 equivalent of N-methyl morpholine dissolved in 2 mL DMF was added and the solution stirred for 5 minutes. The reaction was allowed to come to room temperature, then diluted with six volumes of ethyl acetate. The ethyl acetate was washed with cold water (2x), 0.1 N HCl (3x), 0.2 M Na2CO3 (2x), water (2x) and concentrated brine (1x). The ethyl acetate as concentrated carefully under vacuum, and the residue was recrystallized from CH2Cl2 /hexanes to give 260 mg (62%) of Z-Tyr-Gly-Gly-Phe-OCH2CN. Amino acid analysis: tyr1.0, gly1.9, phe0.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]O)[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2].P(Br)(Br)[Br:25]>COCCOC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][Br:25])[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CO)ccc1Cl
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1Cl

Procedure:
To [5-(4-bromo-2-hydroxymethyl-phenoxy)-2-chloro-phenyl]-acetic acid ethyl ester (0.3 g, 0.7 mmol) in DME (10 mL) was added phosphorus tribromide (0.11 mL, 1.2 mmol). The mixture was worked-up to give the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:14]([CH3:15])=[CH:13][C:12]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: C/C=C/C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)c1ccc(NC(C)=O)nc1
Temperature: 100 °C

Procedure:
A mixture of N-(5-bromopyrid-2-yl)acetamide (31.4 g, Reference Example 23), ethyl crotonate (37.0 mL), triethylamine (33 mL), tetrakis(tri-o-tolylphosphine)palladium(0) and tetrabutylammonium bromide (9.36 g) in dimethylformamide (250 mL) was heated at 100° C. under an argon atmosphere for 48 hours. The reaction mixture was cooled and then evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, then dried over magnesium sulphate and then evaporated. The resulting light brown solid was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give the title compound (27.3 g) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[NH:8][CH3:9].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:5]1[N:4]=[C:3]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:2]([CH:17]=[CH2:18])=[C:7]([NH:8][CH3:9])[N:6]=1
Reactant: CNc1nc(Cl)nc(C(=O)N(C)OC)c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(NC)nc(Cl)nc1C(=O)N(C)OC
Yield: 27.7 %

Procedure:
A solution of 5-bromo-2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide (100 mg), tributyl(vinyl)stannane (113 mg), tetrakis (23 mg) in toluene (1.6 mL) was heated at 95° C. for 12 h, and the solvent was removed. The residue was purified by preparative TLC eluting with 50% EtOAc/Hexanes to give the title compound as a colorless oil (23 mg). LC-MS (M+H)+=257.06.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Br)[CH:3]=1.C(OC(N1CCC(NC2C=CC(C#N)=CC=2OC2C=CC=CC=2Br)CC1)=O)(C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[C:22]3[C:17]([S:16][C:4]=2[CH:3]=1)=[CH:18][CH:19]=[CH:20][CH:21]=3
Reactant: CN1CCC(Nc2ccc(Br)cc2Sc2ccccc2Br)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2Oc2ccccc2Br)CC1
Product: CN1CCC(N2c3ccccc3Sc3cc(Br)ccc32)CC1

Procedure:
Using an adaptation of the method described in Procedure 4, substituting [4-bromo-2-(2-bromophenylsulfanyl)-phenyl]-(1-methyl-piperidin-4-yl)-amine, 3e for 4-[2-(2-bromophenoxy)-4-cyanophenylamino]-piperidine-1-carboxylic acid tert-butyl ester, 3a, the title compound 3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e was obtained. MS m/z (MH+) 375.1/377.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.C(N(CC)CC)C.[NH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41]>CCOCC.C(OCC)(=O)C.O>[C:40]([NH:39][CH2:38][CH2:37][NH:36][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:5]=4[C:6]=3[CH:7]=2)=[C:15]([CH3:23])[CH:16]=1)(=[O:42])[CH3:41]
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: CC(=O)NCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCCNC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and triethylamine (2.5 eq.) in ether (0.05 M) was added N-(2-aminoethyl)acetamide (5.0 eq.). The reaction mixture was stirred for overnight. Then the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give N-(2-acetamidoethyl)-4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzamide as a white solid. 1H NMR (CDCl3): δ 8.61 (s, 1H), 8.38 (s, 1H), 8.07 (d, 1H), 7.65 (s, 1H), 7.51-7.56 (m, 2H), 7.10-7.16 (m, 2H), 6.25 (br, 2H), 3.50-3.59 (m, 4H), 3.08-3.16 (m, 4H), 2.62 (s, 3H), 2.52 (s, 3H), 2.35 (s, 3H). LRMS [M+H]=455.2.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][C:21]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[C:24]1([C:21]2([C:30]3[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=3)[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2ccccc2)(c2ccc(O)cc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Oc1ccc(C2(c3ccccc3)CCNCC2)cc1

Procedure:
4-(4-Hydroxy-phenyl)-4-phenyl-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (270 mg, 0.57 mmol) was treated with a solution of piperidine in DMF (20%, 5 mL) for 2 h. TLC indicated full conversion of the starting material. Concentrated in vacuo to a solid. Worked-up by flash chromatography. LC-MS indicated formation of a complex mixture. The title product was isolated in an analytical amount. LC/MS purity (UV/MS): 90/90%, Rt 3.15 min. M+1: 254
Reaction SMILES: C([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])(C)C.C(N(C(C)C)CC)(C)C.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[C:44](Cl)=[O:45]>ClCCl>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[C:44]([NH:29][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([OH:28])=[C:17]([N:18]=[N:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:8]([S:5]([OH:4])(=[O:7])=[O:6])=[CH:9]2)=[CH:14][CH:13]=1)=[O:45]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N=Nc2c(S(=O)(=O)O)cc3cc(NC(=O)c4ccc(OC)c(OC)c4)ccc3c2O)cc1
Reaction time: 16 h

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo-napthalene-2-sulfonic acid isopropyl ester (Example 6, 100 mg, 0.24 mmol ) was dissolved in dichloromethane (15 mL) and diisopropylethylamine (84 μL, 62 mg, 0.48 mmol). 3,4-Dimethoxybenzoyl chloride (56 mg, 0.28 mmol) was added under nitrogen and the reaction mixture was allowed to stir for 16 h. The solution was washed with water, 1N HCl, and saturated sodium bicarbonate solution. The organic layer was dried with MgSO4 and concentrated. This concentrate was purified by chromatography (silica gel, eluent: 50% ethyl acetate/hexane) to provide the sulfonic acid, isopropyl ester (27 mg, 0.047 mmole, 17%). This ester (16 mg, 0.028 mmole) was suspended in 2-butanone (0.5 mL) and sodium iodide (6 mg, 0.041 mmole) was added. The resulting suspension was heated with stirring to 60° C. for 72 h. The solvent was removed under a stream of nitrogen. The remaining solid was suspended in acetone and filtered to provide the title compound (9 mg, 0.016 mmole, 67%, calculated from the isopropyl ester) as a red solid: NMR (DMSO-d6): δ 16.30 (s, 1H), 10.39 (s, 1H), 8.26 (d, J=9 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 2H), 7.68 (d, J=9 Hz, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.10 (m, 3H), 3.95 (m, 9H): Analytical HPLC: 82% pure: MS (ES-NEG): [M−H] 536.