Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Yield: 30.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.582 g, 1.38 mmol) was dissolved in acetonitrile (15.0 mL), and the solution was treated with pyrrolidine (2.30 mL, 27.8 mmol), acetic acid (1.60 mL, 27.8 mmol) and sodium triacetoxyborohydride (0.876 g, 4.13 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.200 g, 30%).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>CN(C)C(=O)C>[Cl:17][C:9]1[C:8]2[C:7](=[O:18])[C:6]3[C:15](=[C:2]([NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)CCN
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Solvent: CC(=O)N(C)C
Product: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
A mixture of 1,5-dichloro anthraquinone (5.0 g, 18.0 mmol), N,N-dimethylacetamide (30 mL) and N,N-dimethylethylenediamine (2 mL, 18 mmol) was stirred at room temperature for 1 hour and then heated in an oil bath (T=100° C.) for 45 minutes. Reaction mixture was cooled and filtered. To the filtrate petroleum ether (50 mL) was added and combined mixture was stirred at 4° C. over night. Precipitated solid was removed by filtration and supernatant was evaporated to dryness, co-evaporated with chloroform and dried under vacuum. The crude dye was then purified on Biotage SP4 system using a gradient of methanol in chloroform. Appropriate fractions were combined and evaporated to dryness to provide Compound 17 (1.0 g) as a red solid. Rf (9:1 CHCl3/MeOH): 0.46; Abs (max, PBS)=500 nm. The structure of Compound 17 is given below:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][C:25]([NH:27]C(=O)OC(C)(C)C)=[N:24][CH:23]=2)[C:19]2[C:35](=[O:49])[N:36](CC3C=CC(OC)=CC=3OC)[CH2:37][C:18]=2[C:17]=1[F:50])=O)(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][C:25]([NH2:27])=[N:24][CH:23]=2)[C:19]2[C:35](=[O:49])[NH:36][CH2:37][C:18]=2[C:17]=1[F:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnc(NC(=O)OC(C)(C)C)s4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)s1

Procedure:
A solution of tert-butyl (5-(6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclo-hexyl)amino)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,3-thiazol-2-yl)carbamate (41.5 mg, 0.058 mmol) in TFA (5 mL) was heated to 65° C. for 3 h. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF (6.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (10-20% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to yield the title compound as a TFA salt (6.7 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-2.11 (m, 9 H), 3.73 (br s, 2 H), 4.19 (d, J=3.79 Hz, 1 H), 4.41 (d, J=3.03 Hz, 2 H), 6.95 (d, J=3.03 Hz, 1 H), 7.77 (br s, 2 H), 8.44 (s, 1 H), 8.93 (s, 1 H). [M+H] calc'd for C16H19FN6OS, 363; found, 363.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:19](=[O:22])[CH:20]=[CH2:21])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of freshly prepared 4-nitrobenzylamine (3.8 g) in dry dichloromethane (100 ml) containing triethylamine (3.5 ml) was added dropwise to acryloyl chloride (2.2 ml) in dry dichloromethane (100 ml), over 20 min during which time the temperature was kept between -15° and -7°. The reaction mixture was stirred at this temperature for 0.5 h. and then allowed to reach room temperature over a period of 1.25 h. The resulting solution was washed with 2N hydrochloric acid (50 ml), water (50 ml), aqueous 8% sodium bicarbonate solution, and water (50 ml), dried (MgSO4) and evaporated to dryness to afford a solid (3.89 g). This which was triturated with cyclohexane (about 400 ml) to give the title compound as a powder (3.654 g) m.p. 119°-121°.
Reaction SMILES: Br[C:2]1[C:26](=[O:27])[N:25]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH:21]([CH3:23])[O:20][CH:19]([CH3:24])[CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:33].C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC>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>[CH:28]1([N:25]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:18][CH:19]([CH3:24])[O:20][CH:21]([CH3:23])[CH2:22]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:33])=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[C:26]2=[O:27])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)OC(C)C4)cn3)ncc12
Reactant: C=C(OCC)[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=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CC(C)OC(C)C4)cn3)nc2n(C2CCCC2)c1=O

Procedure:
6-Bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.062 g, 0.121 mmol), tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.068 mg, 0.188 mmol) were dissolved in toluene (2 mL) and slowly brought to reflux for 12 hours. Additional tetrakis(triphenylphosphine)palladium (0.010 g) was added and the reaction brought to reflux for 16 hours. The reaction mixture was cooled and purified by silica gel chromatography to 8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-6-(1-ethoxy-vinyl)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.055 g, 90.2%). 1H NMR δ(400 MHz, CDCl3) 8.72 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.99 (d, J=2.9 Hz, 1H), 7.83 (s, 1H), 7.29 (dd, J=2.9, 9.0 Hz, 1H), 5.89 (m, 1H), 4.51 (d, J=2.5 Hz, 1H), 4.17 (d, J=2.4 Hz, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.83 (m, 2H), 3.37 (d, J=10.3 Hz, 2H), 2.44 (dd, J=10.5, 10.5, 2H), 2.41 (s, 3H), 2.34 (m, 2H), 2.06 (m, 2H), 1.84 (m, 2H), 1.65 (m, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.26 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([C:12]1[N:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31](S(C)(=O)=O)[C:30]([CH2:37][OH:38])=[C:29]([F:39])[CH:28]=3)=[CH:23][C:22]=2[F:40])[CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[N:16]=1)([CH3:11])[CH3:10].[C:41]([O:45][P:46]([O:53][CH2:54][C:55]1[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=1)[C:58](O)=[O:59])([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH3:44])([CH3:43])[CH3:42].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:49]([O:48][P:46]([O:53][CH2:54][C:55]1[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=1)[C:58]([O:38][CH2:37][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([N:13]3[CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[N:16]=[C:12]3[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])([CH3:11])[CH3:10])=[C:22]([F:40])[CH:23]=2)=[CH:28][C:29]=1[F:39])=[O:59])([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OP(=O)(OCc1cccc(C(=O)O)c1)OC(C)(C)C
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(CO)c(S(C)(=O)=O)c3)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCc1cccc(C(=O)OCc2ccc(-c3ccc(-n4cc(C(C)(C)O)nc4C(C)(C)c4c(Cl)cccc4Cl)c(F)c3)cc2F)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a stirred solution of 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol (prepared in the manner described in PCT Publication No. WO 2010/138598, 0.1 g, 0.16 mmol) in CH2Cl2 (2 mL) was added 3-((di-tert-butoxyphosphoryloxy)methyl)benzoic acid (140 mg, 0.40 mmol), DMAP (4 mg, 0.33 mmol) and DCC (86 mg, 0.42 mmol). The reaction mixture was stirred at rt. After 15 h, the reaction mixture was filtered, washed with CH2Cl2 (2×10 mL), and the solvents were removed under reduced pressure to yield the crude material. The crude product was purified by column chromatography (basic alumina, EtOAc:Hexane) to afford (4′-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-3,3′-difluorobiphenyl-4-yl)methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate (95 mg, 0.10 mmol, 62%). LCMS: (Ascentis Express C8 (50×2.1 mm-2.7 μm); Solvent A=10 mM NH4COOH in 98% H2O and 2% acetonitrile; Solvent B=98% acetonitrile and 2% 10 mM NH4COOH in H2O; gradient 0% (1.5 min) then to 100% (1.5-3.2 min), 100% (3.2-4 min) B over 4 min), retention time: 2.22 min; LCMS (MM-ES+APCI), flow 1 mL/min, m/z 937.2.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1>C(O)C>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(C2=CCOCC2)cn1
Solvent: CCO
Product: Nc1ccc(C2CCOCC2)cn1

Procedure:
The title compound was prepared as described in example 61, substituting tert-butyl-6-[3-(8-fluoro-quinolin-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylate by 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine and by using ethanol as solvent.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18](O)=[O:19])[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:44][C@@H:45]([C:48]1[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[C:50]([Cl:56])[CH:49]=1)[CH2:46][CH3:47].C(N(CC)CC)C>CN(C)C=O>[Cl:56][C:50]1[CH:49]=[C:48]([C@H:45]([NH:44][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:19])[CH2:46][CH3:47])[CH:55]=[CH:54][C:51]=1[C:52]#[N:53]
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccc(C#N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then 4-((R)-1-amino-propyl)-2-chloro-benzonitrile hydrochloride (68 mg, 0.3 mmol) and triethylamine (60 mg, 0.6 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 82 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-cyano-phenyl)-propyl]-amide as white solid. LC/MS (method 2): Rt=1.24 min; m/z=455.08 (M+H+). 1H-NMR: δ (ppm)=8.20 (1H, d), 7.94 (1H, d), 7.70 (1H, s), 7.50 (1H, d), 7.24 (1H, s), 4.95 (1H, d), 4.82-4.92 (2H, m), 4.20-4.29 (2H, m), 3.70-4.00 (5H, m), 2.07 (1H, m), 1.97 (1H, m), 1.74-1.85 (3H, m), 1.57 (1H, m), 1.19 (3H, d), 0.89 (3H, t).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]([CH3:9])[CH2:7][C:6](=[O:10])[NH:5]1)[CH3:3].OO.O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][CH:2]([N:4]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[NH:5]1)[CH3:3]
Reactant: CC(C)N1NC(=O)CC1C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]n1C(C)C
Temperature: 22.5 °C
Reaction time: 15 h

Procedure:
1-(1-methylethyl)-5-methyl-3-pyrazolidinone (390 g; 2.74 mol) is dissolved in acetic acid (170 ml) with warming. 35% aqueous hydrogen peroxide (260 ml; 3.0 mol) is added within 3 h while keeping the temperature at about 65° C. The reaction mixture is then stirred at about 20 to 25° C. for 15 h. Water (1.2 L) is then added and the pH of the mixture is adjusted to about 7 by means of addition of approx. 1 L 50%-weight aqueous sodium hydroxide solution. Upon cooling to 5° C. the reaction mixture is filtered. The product is washed with water and dried at about 50° C. Colourless crystals are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li+].CC([N-]C(C)C)C.[CH3:19][S:20](=S)(OC)=O>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([S:20][CH3:19])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: COS(C)(=O)=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Cl)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of compound 6.2 (5 mmol) in dry THF (25 mL) was added LDA (6 mmol, 2.0 M in heptane/THF/ethylbenzene) at −78° C. under an atmosphere of N2. After stirring at −78° C. for 30 minutes, the mixture was transferred to a pre-cooled solution of methyl methanethiosulfonate (8 mmol) in of dry THF (10 mL) at −78° C. The resulting mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of several portions of sat. aq. NH4Cl, concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was separated, dried and concentrated to give a residue that was purified by flash column chromatography on silica gel to give 4-chloro-6-methylsulfanyl-thieno[3,2-d]pyrimidine (compound 63.1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:4]=1>Br.C(O)(=O)C>[CH3:12][S:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)(=[O:10])=[O:11]
Reactant: COc1cccc(S(C)(=O)=O)c1
Agent: Br
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C

Procedure:
1-Methoxy-3-(methylsulfonyl)benzene (300 mg, 1.61 mmol) was suspended in 1.6 mL aqueous hydrobromic acid (48% w/w) and 1.6 mL acetic acid. The mixture was heated under reflux for 24 hours. The reaction was cooled back to room temperature and concentrated. The residue was purified by column chromatography through a 40 gram biotage silica gel cartridge eluting with 40-70% ethyl acetate/hexanes (gradient) to give the product as white solid. LRMS calc: 172.0; obs: 173.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:30]=[CH:29][C:23]2[O:24][C:25]([F:28])([F:27])[O:26][C:22]=2[CH:21]=1>>[F:28][C:25]1([F:27])[O:24][C:23]2[CH:29]=[CH:30][C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])=[CH:21][C:22]=2[O:26]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC1(F)Oc2ccc(CBr)cc2O1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)OC(F)(F)O2

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 5-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 406.17 g/mol.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([CH2:22]CS([O-])(=O)=O)[C@@H:18]([CH2:28]CS([O-])(=O)=O)[C@@H:17]2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[CH2:43]([N:50]1[CH2:28][C@@H:18]2[C@H:19]([CH2:20][CH2:21][C@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)[CH3:14])[C@H:17]2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:22]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](CCS(=O)(=O)[O-])[C@@H](CCS(=O)(=O)[O-])[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCc1ccccc1
Solvent: CCO
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
In a pressure tube was placed a solution of crude [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(methylene) dimethanesulfonate (step H) in ˜20 mL ethanol and 1.2 mL (˜3 equiv.) benzylamine. The pressure tube was sealed and heated at 150° C. in an oil bath for 3 hr. The tube was cooled to RT and opened. The resulting mixture was transferred to a round bottom flask and the solvent removed under vacuum. The residue was diluted with 100 mL EtOAc, washed with 20 mL 5N aq. NaOH, dried over MgSO4 drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to give 1.6 g of the title compound. 1H-NMR (CDCl3): δ: 7.35-7.20 (5 H, m), 7.50 (2 H, s), 6.97 (2 H, m), 6.85 (2 H, t, J=8.2 Hz), 4.42 (1 H, t, J=6.0 Hz), 3.75 (2 H, d, J=13.4 Hz), 3.50 (2 H, d, J=13.4 Hz), 3.30 (1 H, m), 2.96 (1 H, m), 2.52 (3 H, m), 2.19 (2 H, m), 1.98 (1 H, m), 1.97 (1 H, m), 1.86 (2 H, m), 1.57 (1 H, m), 1.33 (3 H, t, J=6.0 Hz), 1.30 (1 H, m). MS: (MH)+ 566.0.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[CH:13]=[N:12]2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:9][C:8](=[O:10])[CH:7]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[CH:13]=[N:12]1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(O)cc1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CC1CCCC1)n1ncc(O)cc1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 3-cyclopentyl-2-(4-hydroxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (12.5 g, 47.6 mmol) in methanol (150 mL) was treated dropwise with thionyl chloride (7.1 g, 59.5 mmol). The mixture was stirred at reflux for 1 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The resulting residue was partitioned between water and ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo to afford 3-cyclopentyl-2-(4-hydroxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester as a light yellow oil (10.5 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([O:31][C:32]1[C:37]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:35]2[CH:36]=[C:37]([NH:38][S:39]([C:42]3[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=3)(=[O:41])=[O:40])[C:32]([O:31][CH2:29][CH3:30])=[N:33][CH:34]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 28 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (54 mg, 0.12 mmol) was treated with N-(2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-hydroxybenzenesulfonamide (116 mg, 0.18 mmol), sodium carbonate (30 mg, 0.28 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (32 mg, 0.04 mmol) according to the method described in Example 3 to give 22 mg (27% yield) of the title compound. Purity 100%. LRMS (m/z): 654 (M+1)+. 1H NMR (400 MHz, CD3OD δ 7.88 (m, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.65-7.42 (m, 7H), 7.38 (dd, J=7.6, 1.2 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.33 (m, 1H), 4.23 (q, J=6.9 Hz, 2H), 2.42 (s, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH2:19][NH:20][C:21]([NH2:34])=[N:22][C:23]([C:25]2[C:30]([NH2:31])=[N:29][C:28]([NH2:32])=[C:27]([Cl:33])[N:26]=2)=[O:24])([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.Cl>CO.[OH-].[Na+]>[NH2:31][C:30]1[C:25]([C:23]([N:22]=[C:21]([NH2:34])[NH:20][CH2:19][C:8]2([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:7][CH2:6][N:5]([CH2:4][C:3]([OH:35])=[O:2])[CH2:10][CH2:9]2)=[O:24])=[N:26][C:27]([Cl:33])=[C:28]([NH2:32])[N:29]=1
Reactant: COC(=O)CN1CCC(CCc2ccccc2)(CNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCC1(CCc2ccccc2)CCN(CC(=O)O)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 145 mg (0.23 mmol) {4-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidin-1-yl}-acetic acid methyl ester (Example 1.16) in 5 ml methanol and 235 μl 4 N NaOH is stirred at 50° C. for 1 hour. Then the solution is acidified with 470 μl 4 N HCl and concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:24])=[CH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:24])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c3ccccc23)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c3ccccc23)CC1

Procedure:
To a solution of tert-butyl-4-(4-aminonaphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate in 50 mL of MeOH was added 10 wt % Pd—C (100 mg). The reaction was degassed to remove air and stirred under 1 atm. H2 until the starting material is consumed. The Pd—C was removed by filtration and the resulting solution was concentrated in vacuo to afford tert-butyl-4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate.