Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:23]=[CH:22][C:8]([N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C[Si]([C:28]#[N:29])(C)C.O>C1COCC1.[Cl-].[Zn+2].[Cl-]>[S:1]([C:5]1[CH:23]=[CH:22][C:8]([NH:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)[C:28]#[N:29])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(-c3ccco3)cc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(-c2ccco2)cc1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of 4-sulfamoyl-N-[4-(2-furyl)benzylidene]aniline (0.37 g, 1.13 mmol) in anhydrous THF (5 mL) at 0° C. was added trimethylsilyl cyanide (0.135 g, 1.36 mmol), zinc chloride (1.36 mL, 1.0 M solution in ether, 1.36 mmol). The temperature of the reaction mixture was then allowed to return to room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water and the whole was extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the subtitle compound (0.288 g). 1H-NMR (DMSO-d6) δ: 7.84-7.78 (m, 3H), 7.65-7.60 (m, 4H), 7.39 (d, J=9 Hz, 1H), 7.04-7.01 (m, 3H), 6.91 (d, J=9 Hz, 2H), 6.62 (dd, J=3, 2 Hz, 1H), 6.16 (d, J=9 Hz, 1H). MS (EI) m/z 353 (M+)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][OH:14].F[C:16]1[C:21]2[N:22]=[C:23]([C:25]3[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][O:14][C:16]1[C:21]2[N:22]=[C:23]([C:25]3[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CO)c(OC)c1
Reactant: Nc1ncccc1-c1nc2c(F)cccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc3oc(-c4cccnc4N)nc23)c(OC)c1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium hydride (1.08 g, 60% in mineral oil) was added to a stirred solution of (2,4-dimethoxyphenyl)methanol (4.54 g) dissolved in tetrahydrofuran (150 ml) over a period of 5 minutes at 0° C. After 30 minutes, 3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (1.547 g) was added and the mixture was heated to reflux for 16 hours. The THF was evaporated, water was added and the resultant solid was filtered and washed with water. The solid was then triturated with diethyl ether and dried with phosphorus pentoxide under reduced pressure to afford 3-[4-[(2,4-dimethoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]pyridin-2-amine (2.32 g) as a solid. NMR Spectrum: (CDCl3) 3.82 (s, 3H), 3.86 (s, 3H), 5.41 (s, 2H), 6.50 (dd, 1H), 6.51 (s, 1H), 6.75 (dd, 1H), 6.91 (d, 1H), 6.96 (bs, 2H), 7.17 (d, 1H), 7.24 (d, 1H), 7.41 (d, 1H), 8.20 (dd, 1H), 8.29 (dd, 1H); Mass spectrum: M+H+ 378
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCN1CCCC1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCN3CCCC3)cc2c1
Yield: 54.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 1-(3-chloropropyl)pyrrolidine (110 mg, 0.75 mmol) were converted to the title compound (138 mg, 55%). MS(ESI+) m/z 336.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.CN1CCOCC1.[CH2:37]([O:41][C:42](Cl)=[O:43])[CH:38]([CH3:40])[CH3:39]>C1COCC1>[F:29][C:7]1[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:42]([O:41][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:43])[N:6]=1
Reactant: CC(C)COC(=O)Cl
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)COC(=O)NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
4-(3-Aminopropyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in THF and treated with N-methylmorpholine and isobutylchloroformate. Extractive work-up followed by chromatography gave 2-fluoro-4-(3-isobutoxycarbonylaminopropyl)-1-triphenylmethylimidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]2[C:7]([CH2:8][C@:9]3([CH2:19]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]3=[O:18])=[CH:6][C:5]=1[CH2:22][C:23](O)=[O:24])([O-:3])=[O:2].B>C1COCC1>[OH:24][CH2:23][CH2:22][C:5]1[CH:6]=[C:7]2[C:20](=[CH:21][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:19][C@:9]1([C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]1=[O:18])[CH2:8]2
Reactant: O=C(O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Agent: B
Solvent: C1CCOC1
Product: O=C1Nc2ncccc2[C@@]12Cc1cc(CCO)c([N+](=O)[O-])cc1C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of [(2S)-6-nitro-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetic acid from Step D (753 mg, 2.22 mmol) in THF (15 mL), at −78° C., was added borane (1 M in THF; 9.1 mL, 9.1 mmol) dropwise. After 5 min, the mixture was warmed to 0° C. and stirring was continued at this temperature for 3 h. The reaction was quenched carefully with 1 N HCl and stirring was continued at ambient temperature. The mixture was adjusted to pH 8 with saturated aqueous NaHCO3 and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH7Cl2:MeOH—100:0 to 80:20, to give the title compound. MS: m/z=326 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:41]([C:38]3[CH:39]=[CH:40][C:35]([Br:34])=[CH:36][CH:37]=3)(=[O:43])=[O:42])[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCNS(=O)(=O)c1ccc(Br)cc1
Yield: 72.4 %

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was reacted with 166 mg 4-bromobenzenesulfonylchloride to give 106 mg 4-tert.-butyl-N-{6-[2-(4-bromobenzenesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.95 min, [M−1]−=691.41.
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1CCN2C(=NCCC2)CC1.[S:45]([C:49]1[CH:50]=[C:51]([O:63][CH2:64][C:65]([OH:67])=O)[C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([S:59]([OH:62])(=[O:61])=[O:60])=[CH:54][CH:53]=2)([OH:48])(=[O:47])=[O:46]>CN(C=O)C>[S:45]([C:49]1[CH:50]=[C:51]([O:63][CH2:64][C:65]([NH2:4])=[O:67])[C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([S:59]([OH:62])(=[O:61])=[O:60])=[CH:54][CH:53]=2)([OH:48])(=[O:47])=[O:46]
Reactant: O=C(O)COc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: NC(=O)COc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Reaction time: 8 h
Yield: 33 %

Procedure:
The dendrimer (DAB-Am-32; 185 mg; Mw: 3,514) dissolved in DMF (10 mL) then added PyBop (1.84 g; 2.1 eq; Mw: 520.4), followed by a solution of DBU (1 mL) and 3,6-disulfo-1-naphthoxyacetic acid (1.22 g; 2 eq; Mw: 362.3) in DMF (10 mL). The reaction mixture was left to stir overnight at R.T under N2. The solvent was removed under reduced pressure. Then purified through a sephadex (LH20) column followed by an Ion-exchange (IR120; Na+) and freeze-dried to yield SPL7320 as a white powder (402 mg, 48%).
Reaction SMILES: O.Cl.[CH2:3]([C:7]1([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6].[OH-].[Na+]>CC(C)=O>[CH2:3]([C:7]1([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1(N2CCCC2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCC1(N2CCCC2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (10.0 ml) and 37% hydrochloric acid (14.0 ml) were added to a solution of 1-(8-butyl-1,4-dioxaspiro[4,5]dec-8-yl)pyrrolidine (2.70 g, 10.1 mmol) in acetone (100 ml) and the mixture was stirred overnight at room temperature. Then 4 M sodium hydroxide solution was added slowly to the mixture until a pH of 10 was achieved. The mixture was extracted with diethyl ether (4×40 ml), the combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. The crude product (2.6 g) was purified by flash chromatography (260 g, 30×5.6 cm) with ethyl acetate/methanol (9:1). Yield: 1.06 g (47%), brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C#N)c4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.5 %

Procedure:
To a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (47 mg, 0.15 mmol), prepared as described in Example 113A, in THF (3 ml) was added DMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (89 mg, 0.3 mmol). The reaction mixture was stirred at rt for 24 h. Concentration under reduced pressure gave a residue which was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (14.9 mg, 20%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.66 (s, 6H), 3.99 (s, 6H), 6.92 (d, J=8.7 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.30-7.40 (m, 4H), 7.57-7.66 (m, 4H), 8.56 (s, 1H), 8.90 (d, J=7.5 Hz, 2H); LC-MS (ESI) m/z 484 (M+H)1
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH:20]([Cl:22])[CH3:21].O>CN(C=O)C>[Cl:22][CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:6]1[CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: CC(Cl)CCCBr
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(CCCC(C)Cl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-methyl-2,4(1H,3H)-pyrimidinedione (thimine, 500 mg) and K2CO3 (548 g) in dry DMF (15 mL) was stirred for 1 hour at room temperature. 1-bromo-4-chloropentane (0.548 mL) was then added and the mixture was stirred at room temperature for 4 hours. Water was then added and the resulting mixture was extracted with dichloromethane. The aqueous phase was acidified to pH 7 with aqueous 2% HCl solution and extracted with DCM. The organic phases were dried and concentrated in vacuo. The crude product was purified by a silica SPE cartridge eluting with DCM/MeOH from 98/2 to 95/5 to give the title compound (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[CH:5]=1.[ClH:22]>CO>[ClH:22].[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(CCCN)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-(3-tert-butoxycarbonylamino-propyl)-benzoic acid methyl ester (565 mg) in MeOH (25 mL) was cooled to 0° C. and the solution was saturated with HCl (g). The reaction was stirred at room temperature for 1.5 h and was concentrated in vacuo to provide the title amine (399 mg). MS 194 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[Cl:23]N1C(=O)CCC1=O>ClCCl.O1CCOCC1>[Cl:23][C:10]1[C:11](=[O:14])[CH2:12][CH2:13][C:9]=1[NH:8][C@@H:7]1[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]([CH3:22])([CH3:21])[C@H:2]1[OH:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=C(Cl)C(=O)CC2)[C@@H]1O

Procedure:
A solution of 150 mg of the title compound of example 5 in 5 ml of dichloromethan and 5 ml of dioxan is mixed with 77 mg of N-chloro-succinimide. After 50 minutes at room temperature the solution is poured on water and the organic components are extracted with dichloromethane/ethanol. Recristallisation of the raw product obtained after concentration yields white crystalls of the title compound having a m.p. of 288°-89° C.
Reaction SMILES: [Br:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.[Cl:33]CCl>>[Br:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:33])=[CH:7][CH:6]=1
Reactant: Oc1ccc(C#CCBr)cc1
Reactant: ClCCl
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C#CCBr)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of 4-(3-bromo-prop-1-ynyl)-phenol (5.0 g, 30.12 mmol) dissolved in dichloromethane, 8.3 g (31.63 mmol, 1.05 eq) of triphenylphosphine was added and the solution was cooled to 0° C. Bromine (1.55 mL, 30.12 mmol, 1.0 eq) was added dropwise and the reaction was warmed to room temperature. The reaction was then diluted with dichloromethane, washed with sodium hydrosulfite pentahydrate, washed with brine, dried over MgSO4 and concentrated. The residue was purified via flash chromatography using 4:1 hexane:ethyl acetate to afford 5.56 g (80%) of 1-(3-bromo-prop-1-ynyl)-4-chloro-benzene as an amber oil. Electrospray Mass Spec 280.4 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=3)[NH:9][C:8]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:25]([O:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:30])[CH3:26]>>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=3)[NH:9][C:8]=2[C:21]([NH:30][C@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1

Procedure:
Ethyl N-{[3-phenyl-5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}-L-phenylalaninate was prepared from 3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid and L-phenylalanine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as a pale yellowish solid: 1H NMR (DMSO-d6) δ 1.12 (t, J=7.0 Hz, 3 H), 2.93 (dd, J=13.5, 6.2 Hz, 1 H), 3.05 (dd, J=13.5, 8.0 Hz, 1H), 4.08 (q, J=7.0 Hz, 2 H), 4.70 (dd, J=8.0, 6.2 Hz, 1 H 6.21 (t, J=2.0 Hz, 1 H), 6.95-7.05 (m, 1 H), 7.20-7.60 (m, 16 H), 11.89 (s, 1 H); MS (ESI) m/z 478 (MH+); MS (ESI) m/z 476 ([M-H]−); HRMS calcd for C30H28N3O3: 478.2131; found (ESI+): 478.2113; Anal. calcd for C30H27N3O3: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.30; H, 5,79; N, 8.72.
Reaction SMILES: C([CH:5]1[C@@:9]2([CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH2:8][C@@H:7]([C:21]([OH:23])=[O:22])[N:6]1[C:24](=[O:39])[C@@H:25]([NH:30][C:31]([O:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:32])[C:26]([CH3:29])([CH3:28])[CH3:27])(C)(C)C.N1CCC[C@H]1C(O)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:34]1([O:33][C:31]([NH:30][C@@H:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]([N:6]2[C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][C@@:9]3([CH2:13][C:12](=[O:14])[N:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10]3)[CH2:5]2)=[O:39])=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)C1N(C(=O)[C@@H](NC(=O)OC2CCCC2)C(C)(C)C)[C@H](C(=O)O)C[C@]12CC(=O)N(c1ccccc1)C2
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@]2(CC(=O)N(c3ccccc3)C2)C[C@H]1C(=O)O
Yield: 100 %

Procedure:
The protected proline (3S,5R)-tert-butyl-2-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonane-3-carboxylate (H6a) (9.2 mg, 17 μmol) was dissolved in CH2Cl2 (1.0 ml) and treated with trifluoroacetic acid (0.3 ml) for 4 hrs at room temperature. The reaction was concentrated to dryness under high vacuum to give (3S,5R)-2-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonane-3-carboxylic acid (I6a) (17 μmol). The minor diastereomer (3S,5S)-2-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonane-3-carboxylic acid (I6b) (5 μmol) was obtained in similar fashion.
Reaction SMILES: C([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]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6]([NH2:5])=[O:7])=[CH:9][NH:10][C:11]4=[N:12][CH:13]=3)=[N:18][N:19]2[CH2:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Temperature: 80 °C
Yield: 23.9 %

Procedure:
N-tert-Butyl-2-(6-fluoro-1-(2-morpholino-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (42 mg, 68.9 μmol) was placed in a sealed tube and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (785 mg, 531 μL, 6.89 mmol) was added and the tube was sealed and the mixture heated at to 80° C. After 15 h the mixture was cooled and concentrated in vacuo. Recrystallization from dichloromethane/methanol and cyclohexane gave 2-(6-fluoro-1-(2-morpholino-2-oxoethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (7 mg, 16.5 μmol, 24.0%) as a white powder. MS (M−H)−=422; 1H NMR (DMSO-d6) δ: 8.42 (s, 1H), 7.72 (dd, J=8.9, 5.1 Hz, 1H), 7.65 (s, 1H), 6.73 (d, J=9.4 Hz, 1H), 6.37-6.47 (m, 1H), 4.82 (s, 2H), 2.89-3.09 (m, 6H), 2.82 (d, J=4.9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7](C)C(=O)C)=[CH:4][C:3]=1C=O.[CH:16]1(N)[CH2:18][CH2:17]1.[BH4-].[Na+]>C1COCC1>[CH3:17][CH2:16][CH2:18][CH2:12][CH2:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(=O)N(C)Cc1ccc(Cl)c(C=O)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(4-chloro-3-formylbenzyl)-N-methylacetamide from the previous step (1 eq.) in THF (0.08 M) was added cyclopropylamine (2 eq.) and freshly activated 3A molecular sieves. The resulting mixture was stirred at RT for 48 h. The molecular sieves were then filtered off and the filtrate was evaporated in vacuo. The resulting residue was taken up in methanol (0.07 M) and added sodium borohydride (2 eq.). After 2 h of stirring at RT, the reaction was quenched by the addition of 1 N aq. HCl. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The organic layer was separated and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:28])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A solution of 5-chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) in dry pyridine (2.5 ml) and dry tetrahydrofuran (50 ml) was cooled. To the solution was dropwise added a solution of succinic anhydride (1.1 g) in dry tetrahydrofuran (5 ml) under stirring. The mixture was refluxed for 2 hours and then left overnight. The reaction mixture was treated in the same manner as that in Example 6 to yield the title compound as colorless crystals (2.5 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[I-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:27]=[CH:26][C:21]2[B:22]([OH:25])[O:23][CH2:24][C:20]=2[CH:19]=1)[C:12]#[N:13].[H-].[Na+]>O.CN(C)C=O>[CH:5]1([CH2:4][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:27]=[CH:26][C:21]3[B:22]([OH:25])[O:23][CH2:24][C:20]=3[CH:19]=2)[C:12]#[N:13])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
A solution of bromomethyl cyclopropane (0.544 mL, 5.61 mmol), sodium iodide (4.20 g, 28.05 mmol), and N,N-dimethylformamide (30 mL) under a nitrogen balloon were stirred at 70° C. for 3 hours. The reaction was cooled to room temperature and 3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.500 g, 1.87 mmol) and more N,N-dimethylformamide (30 mL) was added. The reaction was cooled to 0° C. in an ice water bath and sodium hydride (0.224 g, 5.61 mmol) was added. The reaction was stirred under nitrogen balloon at 0° C. for 5 minutes and then at room temperature overnight. Water was added to quench excess sodium hydride and the solution was neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 3-(cyclopropylmethoxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.225 g, 37% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.15 (d, J=4.5 Hz, 2H), 0.43 (d, J=7.6 Hz, 2H), 1.06 (septet, J=6.7 Hz, 1H), 3.90, (d, J=6.9 Hz, 1H), 4.91 (s, 2H), 6.95 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 9.12 (s, 1H).