Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].CC(O)=O.[CH:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:31]#[N:32])[CH:28]=2)[CH2:23]1)=O.C([O-])([O-])=O.[Na+].[Na+]>CO>[C:31]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH2:23][CH:22]([CH2:20][NH:10][CH2:9][CH2:8][NH:7][C:6](=[O:11])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:30]2)#[N:32]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1ccc2c(c1)CC(C=O)C2
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCC1Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2-amino-ethyl)-carbamic acid tert-butyl ester (400 mg, 2.5 mmol), NaBH3CN (315 mg, 5.0 mmol) and HOAc (300 mg, 5.0 mmol) in 30 mL MeOH was added 2-formyl-2,3-dihydro-1H-indene-5-carbonitrile (430 mg, 2.5 mmol). The mixture was stirred at RT overnight, and then sat. Na2CO3 (50 mL) was added and stirred for 30 min. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-TLC to give the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:40]1([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:48]1[CH2:49][CH2:50][N:45]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:46][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate 1 a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 1-cyclopentylpiperazine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (74%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([CH2:9][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C)c(C(O)c2ccc(C(F)(F)F)cc2)c1Br
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(C)c(Cc2ccc(C(F)(F)F)cc2)c1Br
Reaction time: 0.35 h

Procedure:
To a solution of (4-bromo-2,5-dimethyl-3-thienyl)[4-(trifluoromethyl)phenyl]methanol (74.0 g, 200 mmol) Example 11, Step 2 and triethylsilane (130 mL, 800 mmol) in 500 mL of dichloromethane at 0° C. under nitrogen is added trifluoroacetic acid (155 mL, 2.00 mol) such as to maintain an internal temperature between 1 and 4.5° C. Most of the volatiles are removed under reduced pressure and the resulting solution poured onto ether (1 L) and a mixture of sat. aq. sodium bicarbonate and water (500 mL). The phases are separated. The organic layer is washed with brine (200 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue is diluted and concentrated twice from toluene (300 mL). The residue is split in two equal parts, diluted with hexanes (each part with 30 mL) and each part is applied onto 330 g silica gel columns for purification with Combi Flash chromatography system (100% hexanes for 5 minutes then going to 5% ethyl acetate/95% hexanes over 21 minutes to afford the desired product as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].CN(C)C=O.[H-].[Na+].I[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCI
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.3 %

Procedure:
653 mg (1.62 mmol) of the above 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one was dissolved ion 20 mL of dimethylformamide under argon atmosphere, 200 mg (5.00 mmol) of sodium hydride (60% oil dispersion) and 0.48 mL (3.2 mmol) of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by medium pressure liquid chromatography to give 422 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(1-hexylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 54%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>>[CH3:21][O:22][CH2:23][C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: COCC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)COC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and methoxyacetyl chloride, there is obtained ethyl N-(methoxyacetyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: 339 (1, M+H), 309 (1), 293 (98), 194 (20), 167 (100);
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[O:31][CH3:32])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cl
Reactant: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.6 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (6 mg, 0.017 mmol) in DCM (5 mL) were added methyl chloroformate (2.66 mg, 0.028 mmol) and triethyl amine (3.35 mg, 0.033 mmol). The mixture was stirred at rt for 10 h. After concentration, the crude was purified by chromatography on silica gel to afford 3.4 mg (46%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.93 (s, 1H), 8.14 (dd, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.44 (m, 1H), 6.12 (s, 2H), 4.42 (t, 2H), 3.69 (s, 3H), 3.60 (m, 2H), 2.39 (s, 3H). LCMS (method B): [MH]+=421, tR=1.95 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>CN(C)C1C=CN=CC=1.CO>[CH2:11]([O:10][C:9]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:13])[CH3:12]
Reactant: NCC1CCNCC1
Reactant: CCOC(=O)OCC
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CCOC(=O)NCC1CCNCC1

Procedure:
The solution of 1.70 g (9.0 mmol) of 4-(ethoxycarbonylamino-methyl)-piperidine (obtained from 4-aminomethyl-piperidine and diethyl carbonate in the presence of 4-dimethylaminopyridine) in 18 ml of methanol was treated with 9.0 ml (9.0 mmol) of 1N methanolic hydrochloric acid. After addition of 0.53 g (3.0 mmol) of 8-methoxy-2-tetralone, the mixture was stirred for a further 5 minutes. 0.20 g (3.3. mmol) of sodium cyanoborohydride was then added and the mixture was stirred for 15 hours at room temperature, followed by standing for 18 days at about +4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[ClH:11].CCOCC.Cl.[Cl:18]N1C(=O)CCC1=O>CCOCC.Cl.C(O)(=O)C>[ClH:18].[Cl:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cnccc1C
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccncc1C(=O)CCl
Yield: 83.2 %

Procedure:
In a 500 mL round bottom flask was placed 1-(4-methyl-3-pyridinyl)ethanone (10.0 g, 74.1 mmol) in 90 mL of Et2O. To this solution was added 88.9 mL of 1M HCl/Et2O (1.2 eq, 88.9 mmol) with stirring and the solution allowed to stir for 1 h at room temperature, at which point, the precipitate was filtered and washed with Et2O. The solid was then dried in vacuo at about 60° C. This HCl salt (12. g, 70.0 mmol) was then dissolved in 70.0 mL of 1M HCl/acetic acid where 9.34 g (1 eq, 70.0 mmol) of N-chlorosuccinimide (NCS) was added and the reaction allowed to stir under Argon at room temperature overnight. At this point, 300 mL of Et2O was added resulting in an off-white precipitate. This was allowed to stir for 1 h at which point the solid was filtered and rinsed with Et2O to provide 12.0 g (83%) of the desired 2-chloro-1-(4-methyl-3-pyridinyl)ethanone hydrochloride. 1H-NMR (DMSO-d6) δ 2.51 (s, 3H), 5.15 (s, 2H), 7.68 (d, 1H), 8.68 (d, 1H), 9.06 (s, 1H); MS GC-MS [MH]+ 169.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]>C1COCC1.O.C1COCC1>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A solution of NaBH4 (0.53 g, 14 mmol) in THF/H2O (4:1) (12 mL) was added dropwise to an ice-cold stirred solution of 4-formylcinnamic acid (2.47 g, 14 mmol) in THF (25 mL), and the mixture was stirred at room temperature for 3 h. The reaction was quenched by adding 4 N HCl (20 mL), and the THF was removed by a rotary evaporator. The solid residue was treated with H2O (20 mL), and extracted with EtOAc (4×50 mL). The EtOAc extracts were washed with H2O (50 mL) and brine (50 mL), and dried. The crude product was recrystallized from EtOAc to afford pure 4-hydroxymethylcinnamic acid 124 (1.3 g, 52% yield) as yellow solid, with its identity verified by 1H NMR (300 MHz, CD3OD).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:36][C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[N:34][CH:33]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:36][C:32]([CH2:30][CH3:31])=[CH:33][N:34]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ncc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191.5 mg; compound B26) and HBTU (167 mg) in DCM (3 ml) is added DIPEA (0.28 ml) and the mixture is stirred for 1 h at RT. After 1 h an additional amount of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (40 mg) is added and the mixture is stirred for 15 min in order to complete the reaction. Subsequently the solvent is removed and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc/MeOH, 97.5/2.5 (v/v)] and afterwards by preparative HPLC to yield the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2.[OH-].[Na+]>CO.O>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3CO)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3CO)nc2c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of (R)-methyl 3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (120 mg, 0.33 mmol, 1.00 equiv) and sodium hydroxide (66 mg, 1.65 mmol, 4.99 equiv) in methanol/H2O (20/5 mL). The reaction was stirred for 5 h at 70° C. and concentrated to dryness. The residue was dissolved in 20 mL H2O and washed with 10 mL EtOAc. The pH of the aqueous layer was adjusted to 7 with 1N HCl and extracted with DCM/MeOH (10/1, 20 mL×5). The organic layers were combined and dried over Na2SO4 and concentrated to dryness. This resulted in 80 mg (66%) of (R)-3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:9]1([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH:7]=[CH2:8].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:6]([C:9]1([N:22]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=2)(=[O:34])=[O:35])[C:1](=[O:4])[CH:2]=[CH2:3])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[CH:7]=[CH2:8]
Reactant: C=CC(=O)Cl
Reactant: C=CCC1(NCc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1(N(Cc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)C(=O)C=C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Acryloyl chloride (0.360 g, 0.401 mmol) was added at 0° C. to a stirred solution of tert-butyl 4-allyl-4-((1-tosyl-1H-indol-4-yl)methylamino)piperidine-1-carboxylate (0.2 g, 0.382 mmol), diisopropylethylamine (0.32 mL, 1.91 mmol) in DCM (5.0 mL). The reaction mixture was stirred at 0° C. for 30 min and was then allowed to warm to rt and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: 5% ethyl acetate in hexane) to yield the title compound as a white solid (0.16 g, 72%). LCMS RtA=0.774, [M+H-Boc]+=477.9
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.Cl.CCOCC>[N+](C)([O-])=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2cnc3nc(N)nc(N)c3c2)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1

Procedure:
Alternatively, 0.48 g of 2,4-diamino-6-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyrido[2,3-d]pyrimidine was added to a saturated solution of hydrogen chloride in 20 mL of nitromethane at 0°. The reaction mixture quickly became viscous and turned a deep yellow color and after a few minutes of stirring, a granular solid formed. After 1 hour of stirring, 50 mL of ether were added and the precipitate was collected by filtration. The collected solid was dissolved in 50 mL of 10% aqueous sodium carbonate. Acidification with acetic acid then resulted in the separation of a yellow solid which was collected by filtration and dried under reduced pressure; yield 0.31 g (92%) of 2,4-diamino-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine; NMR (Me2SO-d6) delta 6.75 (s, 2H), 7.35, 7.85 (AB q, 4H, J=9 Hz), 8.38 (s, 2H); IR (Nujol) 3400-2300, 3380, 3150, 1700, 1650, 1630, 1590 cm-1.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([O:13]CC)=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[S:3][C:4]([C:11]([Cl:18])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1sc(Cl)nc1C(F)(F)F

Procedure:
A mixture of 36.0 g (0.1554 mole) of the acid of Example 17 and 171 g (1.437 mole) of thionyl chloride were held at reflux for 6 hours. Excess thionyl chloride was removed under reduced pressure and the residue (38.1 g, 98%) was reacted as described in Examples 19-31.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11]Cl)[C:8]([CH2:13]Cl)=[CH:7][C:6]=1[O:15][CH3:16].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>C(O)(=O)C>[C:17]([O:20][CH2:13][C:8]1[CH:7]=[C:6]([O:15][CH3:16])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:10][C:9]=1[CH2:11][O:20][C:17](=[O:19])[CH3:18])(=[O:19])[CH3:18]
Reactant: COc1cc(CCl)c(CCl)cc1OCCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(COC(C)=O)c(COC(C)=O)cc1OCCCl
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of 5.67 g (20 mmol) of 36 in 75 mL of acetic acid was added a solution of 3.5 g of anhydrous sodium acetate (42.7 mmol) in 100 mL of acetic acid. This mixture was refluxed with stirring for 2 h. Solids were removed by filtration and washed with acetic acid. The filtrate was evaporated to approximately 30 mL, then poured into water and extracted with ether. The organic phase was washed with aqueous sodium carbonate, water, and brine. After drying over sodium sulfate, the solution was filtered and evaporated to give 5.69 g (86%) of 2-[(acetyloxy)methyl]-4-(2-chloroethoxy)-5-methoxybenzyl acetate (37) as a white solid, mp 79-80° C.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(OC(F)(F)F)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-trifluoromethoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.96 (d, J=13 Hz, 2H), 2.12 (s, 1H), 2.31 (d, J=13 Hz, 2H), 2.40 (s, 2 H), 3.50 (s, 2H), 3.60 (s, 4H), 4.40 (s, 1H), 7.45-7.51 (m, 1H), 7.56-7.62 (m, 1H), 7.74 (s, 1H), 7.82-7.87 (m, 1H); MS (APCI/NH3) m/z 341 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[N:8][C:9](I)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)C=C.[CH:32]1([C:35]2[C:40]3[N:41]=[CH:42][S:43][C:39]=3[CH:38]=[CH:37][N:36]=2)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.[Cu]I>[Si:25]([O:24][C@H:21]1[CH:18]2[O:19][CH2:20][C@@H:16]([O:15][C:5]3[NH:4][C:12]4[C:7]([N:6]=3)=[N:8][C:9]([C:42]3[S:43][C:39]5[CH:38]=[CH:37][N:36]=[C:35]([CH:32]6[CH2:33][CH2:34]6)[C:40]=5[N:41]=3)=[C:10]([Cl:13])[CH:11]=4)[CH:17]2[O:23][CH2:22]1)([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:26])[CH3:27]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(I)c(Cl)cc21
Reactant: c1cc2scnc2c(C2CC2)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1COC2C1OC[C@H]2Oc1nc2nc(-c3nc4c(C5CC5)nccc4s3)c(Cl)cc2[nH]1
Temperature: 100 °C

Procedure:
Palladium tetrakistriphenylphosphine (200.0 mg, 0.173 mmol) was added to a stirred suspension of [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (500.0 mg, 0.865 mmol, Intermediate 5), 4-cyclopropylthiazolo[4,5-c]pyridine (183.0 mg, 1.038 mmol), cesium carbonate (1.409 g, 4.33 mmol), and copper (I) iodide (99.0 mg, 0.519 mmol) in degassed DMF (3.2 mL). The reaction mixture placed under nitrogen before being heated to 100° C. for 3 h. The reaction mixture was cooled to room temperature and added to EtOAc (80 ml). The mixture filtered and the solids washed with EtOAc (2×30 mL). The filtrate was evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 40 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C27H32ClN5O4SSi 585.16 observed m/e: 586.17 (M+H)+ (Rt 1.18/1.8 min)