Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:45]1([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][NH2:58])=[CH:53][CH:52]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([NH:58][CH2:57][C:54]3[CH:53]=[CH:52][C:51]([CH2:50][N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)=[CH:56][CH:55]=3)=[O:22])[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Reactant: NCc1ccc(CN2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(=O)NCc2ccc(CN3CCCC3)cc2)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 5-({[(4-bromo-2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.09 mmol), EDCI (23 mg, 0.12 mmol) and HOBt (15 mg, 0.11 mmol) in DMF (3 mL) was added 1-[4-(pyrrolidin-1-ylmethyl)phenyl]methanamine (17 mg, 0.09 mmol). The reaction was stirred at ambient temperature for 3 days, then absorbed on to an Isolute SCX-2 cartridge, washing with MeOH and eluting the product with 7M NH3 in MeOH. The filtrate was concentrated in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]5[C:31](=[O:43])[N:32]([C:36]6[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=6)[N:33]=[CH:34][CH:35]=5)=[O:29])=[CH:23][C:22]=4[F:44])[CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.C(O)(C(F)(F)F)=O>>[F:44][C:22]1[CH:23]=[C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:33]=[CH:34][CH:35]=2)=[O:29])[CH:25]=[CH:26][C:21]=1[O:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:12]=[C:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[S:19][C:18]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A round-bottomed flask was charged with N-(4-(2-(1,4-dioxaspiro[4.5]decan-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (13.3 mg, 0.0216 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at room temperature the starting material had been consumed (1 hour). Then the solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (5.3 mg, 42.9%). LRMS (APCI pos): >99% purity, 254 nm, m/e 573 (M+1). 1H NMR (400 MHz, CD3OD) δ 11.84 (s, 1H), 8.46 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.57-7.65 (m, 2H), 7.39 (m, 1H), 7.34 (s, 1H), 7.21-7.30 (m, 3H), 6.49 (d, 1H), 3.45 (m, 1H), 2.34-2.61 (m, 6H), 2.09 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)O1>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:42]2[CH:43]=[CH:44][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:56])[CH3:57])[CH2:51][CH2:50][CH2:49]3)=[CH:46][CH:47]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.800 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (2 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (1.15 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.08 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2×75 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.6 g, 52%). 1H NMR (DMSO-d6) 400 MHz δ 8.41 (s, 1H), 8.04 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.96 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.53-7.48 (m, 2H), 7.45-7.08 (m, 11H), 6.91-6.86 (m, 1H), 6.67-6.62 (m, 1H), 2.45-2.32 (m, 4H), 2.07-1.94 (m, 1H), 1.85-1.73 (m, 1H), 1.28 (bs, 9H); LCMS: 556 [M+H].
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][C:23]#[C:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>ClCCl>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][C:23]#[C:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1OCC#CCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1OCC#CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 64.7 %

Procedure:
Into 35 ml of dichloromethane were dissolved 2.67 g of 4-diphenylmethoxypiperidine, 2.93 g of 1-chloro-4-(2-nitrophenoxy)-2-butyne and 1.68 g of N,N-diisopropylethylamine, and the resultant solution was stirred at room temperature for 20 hours. The reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethyl acetate by silica gel column chromatography to give 2.95 g of oily 4-diphenylmethoxy-1-[4-(2-nitrophenoxy)-2-butynyl]piperidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12](Br)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc3ccccc3c2)c1
Yield: 75 %

Procedure:
A solution of 5-bromoisophthalic acid dimethylester (544 mg, 2 mmol), 2-naphthaleneboronic acid (342 mg, 2 mmol), Pd(OAc)2 (8 mg), tri-o-tolylphosphine (30 mg) and 5 ml Et3N (5 ml) in 10 ml DMF was stirred at 100° C. for overnight The reaction mixture was purified by silica gel column eluted by 20% EtAc in hexane to afford the product (75% yield). 1H NMR (Acetone-d6, 400 MHz), 8.55 (s, 1H), 8.45 (s, 2H), 8.17 (d, 1H), 7.91 (d, 1H), 7.88 (d, 1H), 7.77 (t, 1H), 7.67 (t, 1H), 7.38 (m, 2H), 4.03 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:7]=[CH:6][N:5]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2nccc(Cl)n2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2ccnc(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.91 (d, J=4.8 Hz, 1H), 8.74 (d, J=8.5 Hz, 2H), 8.28 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.65 (d, J=5.3 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH:41]1[CH2:45][CH2:44][C@@H:43]([OH:46])[CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:41]4[CH2:45][CH2:44][C@@H:43]([OH:46])[CH2:42]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: O[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CN4CC[C@@H](O)C4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.3 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), (R)-(+)-3-pyrrolidinol (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of (R)-(+)-3-pyrrolidinol (0.1 mL), and sodium triacetoxyborohydride (0.084 g, 0.40 mmol) were added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the precipitate was collected by filtration and combined with the residue obtained from extraction of the water layer with one portion of dichloromethane (20 mL). The crude mixture was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min). The appropriate fraction was collected, concentrated, and lyophilized to afford N1-{4-[4-amino-1-(4-{[(3R)-3-hydroxytetrahydro-1H-1-pyrrolyl]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.034 g, 0.055 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.34-8.37 (2H, m), 8.15-8.19 (2H, m), 7.98-8.01 (1H, m), 7.85 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=8.0 Hz), 7.48-7.54 (2H, m), 7.44 (1H, s), 7.40 (1H, d, J=8.4 Hz), 4.70 (1H, bs), 4.22 (1H, s), 3.96 (3H, s), 3.63 (2H, s), 2.49-2.72 (3H, m), 2.13-2.41 (1H, m), 1.91-2.06 (1H, m), and 1.53-1.61 (1H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.53 min. MS: MH+ 622.2.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:10]2[CH2:11][N:12]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=[CH:7]1.O.CN(C)[CH:31]=[O:32]>>[CH:31]([C:7]1[O:6][C:10]2[CH2:11][N:12]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=1)=[O:32]
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccoc2C1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of N,N-dimethylformamide, 0.33 ml (3.6 mmol) of phosphorus oxychloride was added under ice-cooling, followed by stirring at room temperature for 0.5 hours. To this mixture, a solution of 1.064 g (3.578 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-6-phenylhexan-1-one in 20 ml of N,N-dimethylformamide was added, followed by overnight stirring at room temperature. After water was added, the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel flush column chromatography (hexane/ethyl acetate=2/1 to 1/1) to yield the desired product.
Reaction SMILES: S(O)(O)(=O)=O.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21].N12CCCN=C1CCCCC2>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:25]([OH:26])=[N:11][C:7]2[N:6]([CH:10]=[CH:9][N:8]=2)[C:20]=1[OH:21]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1F
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1nc2nccn2c(O)c1-c1ccccc1F
Temperature: 100 °C

Procedure:
5 g (27.5 mmol) 1H-Imidazol-2-ylamine sulfate are dissolved in 31.7 mL DMF. 7 g (27.5 mmol) diethyl (2-fluorophenyl)malonate are added. After dropwise addition of 12.3 mL (82.6 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. over night. The DMF is evaporated and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (60 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (3.43 g=48.3%), which is used without further purification. Another crop of 0.41 g (6.1%) is obtained by evaporating the solvent, treating the oily residue with water and 2M HCl. After stirring for five hours the crystals are collected and washed with water.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:10][O:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[N:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:8]
Reactant: COC(=O)c1sccc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sccc1N=CN(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of methyl 3-amino-2-thiophenecarboxylate (1.572 g, 10 mmol) in 5 ml of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was heated at reflux for 2 h and then allowed to cool to room temperature. The resulting mixture was evaporated to give 2.019 g (95%) of orange residue. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.63 (d, J=5.6 Hz, 1H), 6.81 (d, J=5.2 Hz, 1H), 3.67 (m, 3H), 3.00 (s, 3H), 2.93 (s, 3H); LC-MS (ESI) m/z 213.1 (M+1).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@H](N=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](F)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask equipped with a magnetic stir bar and a reflux condenser, to a solution of cis-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate (86 mg, 0.374 mmol) in THF (5.5 mL) was added PPh3 on polystyrene (1.6 mmol/g, 280 mg, 0.448 mmol) and water (0.33 mL). The reaction mixture was stirred at 60° C. for 2 h. The mixture was then filtered and the filtrate dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford cis-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate as a colorless oil. LC-MS-conditions 10: tR=0.45 min; [M-CH3+H]+=190.41.
Reaction SMILES: [CH3:1][Si:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][C:14]3[N:15]([C:16]([CH:19]4[CH2:24][CH2:23][N:22](C(OCC5C=CC=CC=5)=O)[CH2:21][CH2:20]4)=[CH:17][N:18]=3)[C:10]=2[CH:9]=[CH:8]1.C([SiH](CC)CC)C>[Pd](Cl)Cl>[NH:22]1[CH2:21][CH2:20][CH:19]([C:16]2[N:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:36])([CH3:35])[CH3:1])[C:11]=4[N:12]=[CH:13][C:14]3=[N:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1ncc(C3CCN(C(=O)OCc4ccccc4)CC3)n12
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1ncc(C3CCNCC3)n12
Yield: 54.8 %

Procedure:
A solution of benzyl 4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate (0.580 g, 1.15 mmol, prepared using R from 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (Matrix), S from Example #3 Step E, E with TFA, KKKK with PFPAA, D with NaOH, KK), TEA (0.03 mL, 0.229 mmol), palladium (II) chloride (0.020 g, 0.115 mmol) in triethylsilane (18.3 mL, 115 mmol) was heated at about 120° C. for about 8 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The product was purified by silica gel chromatography eluting with a gradient of 0-10% (90:9:1) (MeOH/DCM/DEA) in DCM to give 8-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.234 g, 55%) as a brown oil: LC/MS (Table 1, Method b) Rt=1.93 min; MS m/z: 372 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[H-].[Na+].I[CH2:34][CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>CN(C=O)C>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:36][CH2:35][CH2:34][O:1][CH2:2][C@H:3]2[CH2:14][CH2:13][C:12]3[S:11][C:10]4[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]5[CH2:17][CH2:18][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:20][CH2:21]5)[C:5]=4[C:4]2=3)=[CH:39][CH:40]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Reactant: COc1ccc(COCCI)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCCOC[C@H]2CCc3sc4ncnc(OC5CCC(N(C)C(=O)OC(C)(C)C)CC5)c4c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (940 mg, 2.17 mmol, 1.00 equiv) in freshly distilled DMF (6 mL) was added sodium hydride (60% dispersion in mineral oil, 347.3 mg) slowly at 0° C. under nitrogen. After the addition, the reaction mixture was stirred at room temperature for 30 min. Then 1-[(2-iodoethoxy)methyl]-4-methoxybenzene (2.535 g, 8.68 mmol, 4.00 equiv) was added to the mixture and stirred for 14 hrs at ambient temperature. The reaction was quenched slowly with saturated aqueous NH4Cl and extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give tert-butyl N-(4-[[(3S)-3-([2-[(4-methoxyphenyl)methoxy]ethoxy]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (700 mg, 54%) as a colorless oil. MS: m/z 598 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(3-trifluoromethylphenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-(3-trifluoromethyl-phenyl)-piperidine-1-carboxylate as a light yellow oil; MS: 485 (M)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:25])[NH:7][C:6]1=[O:26])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].Cl>CN(C)C=O.O>[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:11]2[N:10]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:9]3[C:8](=[O:25])[NH:7][C:6](=[O:26])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=3[N:12]=2)=[CH:16][CH:17]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)[nH]c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Temperature: 50 °C
Yield: 41.4 %

Procedure:
A mixture of N-[4-(3-butyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-phenyl]-acetamide (196 mg, 0.55 mmol) in N,N-dimethylformamide (5.0 mL) at 25° C. was treated with sodium carbonate (117 mg, 0.55 mmol) and 2,2-dimethyl-propionic acid chloromethyl ester (0.10 mL, 0.55 mmol). The resulting mixture was warmed to 50° C. for 8 h. At this time, the reaction mixture was poured into a solution of water (2.5 mL) containing a 1N aqueous hydrochloric acid solution (1.65 mL). This solution was extracted with ethyl acetate. The organics were washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:2 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (107 mg, 41.4%) as a yellow foam: FAB-HRMS m/e calcd for C24H31N5O5 (M+H)+ 470.2403, found 470.2408.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]([CH2:7][C@@:8]2([CH3:43])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([NH:24][C@@H:25]5[CH2:29][CH2:28][C@H:27]([C:30](OC)=[O:31])[CH2:26]5)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=3)[C:9]2=[O:42])=[CH:5][CH:4]=1)#[N:2].[NH3:46]>>[C:30]([C@H:27]1[CH2:28][CH2:29][C@@H:25]([NH:24][C:22]([C:19]2([NH:18][C:16]([C:13]3[N:12]4[C@@:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:45][CH:44]=5)([CH3:43])[C:9](=[O:42])[N:10]([C:34]5[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=5)[C:11]4=[N:15][CH:14]=3)=[O:17])[CH2:21][CH2:20]2)=[O:23])[CH2:26]1)(=[O:31])[NH2:46]
Reactant: N
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)C1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)N[C@@H]4CC[C@H](C(N)=O)C4)CC3)n21
Temperature: 80 °C
Reaction time: 65 h
Yield: 55 %

Procedure:
To methyl (1S,3R)-3-({[1-({[(3R)-3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-5-yl]carbonyl}amino)cyclopropyl]-carbonyl}amino)cyclopentanecarboxylate (109.2 mg, 0.168 mmol) was added ammonia (7N in methanol, 4 mL, 28 mmol) and the reaction tube was sealed. The reaction solution was stirred at 80° C. for 65 h. The reaction solution was then cooled to room temperature and concentrated in vacuo. The resultant residue was purified via reverse phase HPLC to afford 58.6 mg of the title compound as a white solid, m/z 634.2 [M+1]+.