Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:12]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Yield: 13.3 %

Procedure:
In THF (400 ml) were dissolved 2,4-difluoronitrobenzene (17.4 g, 109 mmol) and di-tert-butyl malonate (27.0 ml, 120 mmol). Under stirring at 0° C., sodium hydride (60% in oil, 4.82 g, 120 mmol) was added in portions. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was poured in 1.0N-HCl (300 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (20:1 to 10:1) eluate fractions, di-tert-butyl (3-fluoro-4-nitrophenyl)malonate (5.17 g, 13%) was obtained as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:15])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-])=O>CO.[Ni]>[ClH:20].[ClH:20].[NH2:1][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:15])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NCC(O)COc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1N
Product: Cl

Procedure:
1-(2-nitro-4-chlorophenoxy)-2-hydroxy-3-tert.-butylamino propane was hydrogenated in the presence of Raney-nickel in methanol to obtain 1-(2-amino-4-chlorophenoxy)-2-hydroxy-3-tert.-butylamino propane dihydrochloride having a melting point of 260°-262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:31][C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:34]5[CH2:35][CH2:36][C@H:32]([OH:31])[CH2:33]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CC[C@H](O)C5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), (S)-(−)-3-hydroxylpyrrolidine (0.113 g, 1.3 mmol), DIEA (0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to obtain a crude yellow solid, which was washed with methanol to obtain a purified product (0.22 g) in 44.9% yield.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12]([CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH2:29][C:30]4[C:31]([O:37][CH3:38])=[N:32][CH:33]=[C:34]([F:36])[CH:35]=4)=[N:26][CH:27]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:36][C:34]1[CH:35]=[C:30]([CH2:29][NH:28][C:25]2[N:26]=[CH:27][C:22]([CH2:21][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=4)[NH:10][CH:11]=3)=[CH:23][N:24]=2)[C:31]([O:37][CH3:38])=[N:32][CH:33]=1
Reactant: COc1cnc2c(c1)c(Cc1cnc(NCc3cc(F)cnc3OC)nc1)cn2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc2[nH]cc(Cc3cnc(NCc4cc(F)cnc4OC)nc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [5-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (125, 1 equivalent) in 15.0 mL of tetrahydrofuran, tetrabutylammonium fluoride trihydrate (2 equivalent) is added. The reaction is stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([NH2:16])=[C:11]([Cl:17])[N:10]=1.[CH:18](O)=[O:19]>>[Cl:17][C:11]1[C:12]([NH:16][CH:18]=[O:19])=[C:13]([Cl:15])[N:14]=[C:9]([NH:8][CH:5]=[O:7])[N:10]=1
Reactant: O=CO
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Product: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Acetic anhydride (40 ml) was added dropwise over 10 minutes to a mixture of 2,5-diamino-4,6-dichloropyrimidine (8.0 g, 44.7 mmol) and formic acid (100 ml) at 0° C. The mixture was stirred at 20° C. for 4 hours, evaporated to dryness and co-evaporated with toluene. Solidification from acetone-hexane afforded the title compound (6.1 g, 60%). IR: υmax (KBr) 3230, 1715, 1680, 1575, 1550, 1485, 1415 cm-1. Found m/e 233.9695; C6H4N4O2Cl2 requires 233.9709.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:7]=1[NH2:8].[N:15]#[C:16][Br:17]>>[BrH:17].[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:6]2[C:2]3[N:3]([CH2:4][CH2:5][N:1]=3)[C:16]([NH2:15])=[N:8][C:7]=2[CH:9]=1
Reactant: N#CBr
Reactant: COc1ccc(C2=NCCN2)c(N)c1
Product: Br
Product: COc1ccc2c(c1)N=C(N)N1CCN=C21

Procedure:
The procedure used for the preparation of Intermediate C, Step 4 was used to prepare the title compound from 2-(4,5-dihydro-1H-imidazol-2-yl)-5-methoxyaniline (Step 2) and cyanogen bromide as a yellow solid (7.1 g, 56%). HPLC MS RT=1.07 min, [M-HBr+H]+=217.2
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH:18]=1)[CH2:7]P(=O)(OCC)OCC.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][N:21]=2)[CH:18]=1)[CH:7]=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To a suspension of sodium hydride (0.292 g, 12.17 mmol) in THF (10 mL) under inert atmosphere cooled to 0° C. was added diethyl 3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylphosphonate (3.8 g, 8.11 mmol) as a solution in THF (10 mL) dropwise. The reaction was stirred for 30 min at 0° C. and tert-butyl 4-oxopiperidine-1-carboxylate (1.62 g, 8.11 mmol) was added as a solution in THF (10 mL). The reaction was stirred at RT for 5 h. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness to give the title compound (4.22 g, 100%). 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 7.18 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.91 (s, 1H), 6.28 (s, 1H), 3.49 (m, 2H), 3.40 (m, 2H), 2.44 (m, 2H), 2.32 (m, 2H), 1.47 (s, 9H); m/z (513.2, 515.2, M+ H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:45](O)[CH2:46][OH:47]>>[CH3:32][C:2]1([CH3:1])[P:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5][C:6]2([O:47][CH2:46][CH2:45][O:8]2)[CH2:7]1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCCO3)c(C(C)C)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A flask was charged with 3.75 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (8.32 mmol, 1.0 equiv) and 0.16 g of p-toluenesulfonic acid monohydrate (0.84 mmol, 0.1 equiv). The atmosphere was purged with nitrogen and the flask was charged with 80 mL of nitrogen-sparged toluene. To this solution was added 4.6 mL of ethylene glycol (83 mmol, 10 equiv). The reaction flask was equipped with a Dean-Stark trap and warmed to an internal temperature of 110° C. for 2 h under nitrogen atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature under nitrogen gas. The reaction was quenched with 1.6 mL of aqueous 10 wt % sodium carbonate solution and partitioned between 65 mL of heptane and 35 mL of water. The organic solution was washed twice with 20 mL portions of water, concentrated in vacuo with gentle heating and the residue was chased once with heptane. The concentrate was dissolved in 35 g of methanol. Seed crystals were added to induce crystallization, the solvent was removed in vacuo and 16 mL of methanol was added to the crystalline solid. The mixture was stirred overnight at room temperature and the crystalline product was isolated by filtration, washed with methanol and dried in vacuo at 50° C. to give 3.5 g of 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)1,4-dioxa-8-phosphaspiro[4.5]decane (96 area % by HPLC, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH2:17][CH3:18])[C:7]3[N:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Br:1][C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH2:17][CH3:18])[C:7]3[N:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[N:9]([CH3:23])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CCN1c2nc(F)ccc2NC(=O)c2cc(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a solution of the 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (44 g, 130.5 mmol) in DMF (520 mL) was added NaH (4.28 g, 178 mmol), and the mixture was heated to 50° C. for 30 min. The reaction mixture was cooled to room temperature and treated with MeI (24.4 mL, 522 mmol). After 1.5 h, the reaction mixture was poured over ice water. The solid was filtered, washed with water and then hexane, dried under reduced pressure to give the title compound (43.2 g, 94% yield) as dark grey solid.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCCCOc1ccccc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 73.7 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (0.2 mg, 0.7 mmol) and 3-bromopropylphenyl-ether (0.17 mL, 1.1 mmol) in 2 CH3CN/3 CHCl3 (15 mL) were reacted to give the desired product (255 mg, 64%). 1H NMR (400 MHz, CD3OD) δ 7.5 (m, 4H), 7.35 (m, 3H), 7.3-7.2 (m, 4H), 6.9 (m, 4H), 4.07 (m, 3H), 3.8-3.7 (m, 2H), 3.62 (m, 5H), 3.6-2.5 (m, 2H), 2.4-2.3 (m, 2H), 2.3-2.1 (m, 51).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:9][C:10]2[CH:19]=[CH:18][C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=c1[nH]c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(Oc3cc(Cl)ncn3)cc2o1

Procedure:
0.20 g (1.34 mmol) 4,6-dichloropyrimidine, 0.21 g (1.39 mmol) 6-hydroxy-2-benzoxazolinone and 0.20. g (1.45 mmol) potassium carbonate in 2.0 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27]([C:29]2[O:30][C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:33]=2)=[O:28])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Si:1]([O:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[CH2:25][CH:26]([C:27]([C:29]1[O:30][C:31]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:33]=1)=[O:28])[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CCC(=O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(Cc1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)C(=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.6 %

Procedure:
A mixture of 3-[3-(tert-butyldiphenylsilyloxy)phenyl]-1-(4,5-diphenyl-2-oxazolyl)-1-propanone (526 mg), ethyl bromoacetate (1.61 g), and K2CO3 (1.34 g) in N,N-dimethylformamide (2.0 ml) was stirred at room temperature for 5 hours and poured into ethyl acetate-water. The organic layer was separated, washed with water (three times) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford ethyl 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-4-(4,5-diphenyl-2-oxazolyl)-4-oxobutyrate (436 mg) as an oil-(+) APCI-MS (m/z): 694 (M+ +1) IR (Nujol): 1740, 1700, 1600, 1580 cm-1
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1074549 A2) was treated with the 4-phenylpiperidine in N,N-dimethylformamide in the presence of N-ethyldiisopropyl-amine at room temperature to yield the 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3H-pyrimidin-4-one as yellowish solid; m.p. 210-213° C.; MS: [M+H]+=315.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]([F:20])([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:21])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]([F:20])([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:21]
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(N)C(O)CC1
Temperature: 60 °C

Procedure:
A solution of 2-azido-5-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)cycloheptanol (280 mg, 094 mmol) in THF/water (20 mL/4 mL) was treated with triphenylphosphine (270 g, 1.03 mmol) and the mixture was heated at 60° C. behind a blast screen for 18 hr. The solvents were removed under reduced pressure and the residue was purified via a SCX cartridge washing with MeOH and eluting with 3 N NH3 in MeOH to give 2-amino-5-fluoro-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptanol as a colourless oil. To a solution of this oil (256 mg, 0.94 mmol) in dry DCM (20 mL) at 0° C. was added slowly DIPEA (0.49 mL, 2.82 mmol) followed by trifluoroacetic anhydride (0.16 ml, 1.13 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Water (20 mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (30-50% EtOAc/isohexane) gave 2,2,2-trifluoro-N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)acetamide as a pale yellow oil (130 mg, 38% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.07 and 8.06 (2s, 1H), 6.53 (s, 1H), 4.08 and 4.06 (2s, 3H), 4.05-3.92 (m, 2H), 3.06-2.69 (m, 3H), 2.32-1.89 (m, 6H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3([CH3:24])[CH2:23][CH2:22]3)=[C:15]([CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:25]([C:15]1[CH:14]=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=2)[CH:18]=[CH:17][C:16]=1[CH2:19][O:20][C:21]1([CH3:24])[CH2:22][CH2:23]1)([CH3:27])[CH3:26]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(COC3(C)CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1COC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution methyl{4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl }-acetate (Compound 140, 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded of the title compound as a colorless solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH2:60])[CH2:59][CH2:58]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:68])([F:67])[F:66])[CH:45]=1>CN(C=O)C>[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH:60][C:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=4)=[O:34])[CH2:58][CH2:59]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:66])([F:67])[F:68])[CH:45]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cccc(C)n4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
28 μL (0.20 mmol) of TEA and 118.8 mg (0.30 mmol) of HATU were added to a solution of 27.7 mg (0.20 mmol) of 6-methylpicolinic acid in 5 mL DMF and the mixture was stirred for 5 min at RT. Then 112 μL (0.81 mmol) of TEA and 100 mg (0.20 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) were added and the mixture was stirred overnight at RT. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:11][N:12]([CH3:18])[C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([N:15]2[CH2:16][CH2:17][C@H:13]([N:12]([CH3:18])[CH3:11])[CH2:14]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1F
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)[C@H]1CCN(c2c(Br)cccc2C=O)C1
Temperature: 85 °C
Yield: 45.5 %

Procedure:
A 50 mL round bottom flask was charged with a magnetic stir bar, 3-bromo-2-fluorobenzaldehyde (0.555 g, 2.73 mmol), (S)-N,N-dimethylpyrrolidin-3-amine (0.312 g, 2.73 mmol), DMSO (5.47 ml), and potassium carbonate (0.378 g, 2.73 mmol). The mixture was heated to 85° C. overnight with stirring. The reaction was allowed to cool to ambient temperature, was diluted with water, and extracted into methylene chloride. The combined organic extract was dried with MgSO4, filtered, and conc. in vacuo to provide the product which was purified via silica gel chromatography (40 g) using ethyl acetate/MeOH (10:1) as eluent to afford (S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde (0.369 g, 45.4%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>>[CH:40]1([N:32]2[C:30]3[N:31]=[C:26]([NH:24][C:21]4[N:20]=[CH:19][C:18]([N:11]5[C:12](=[O:17])[CH2:13][CH:14]6[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:16][CH2:15]6)[CH2:10]5)=[CH:23][CH:22]=4)[N:27]=[CH:28][C:29]=3[CH:34]=[C:33]2[C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[CH2:41][CH2:42][CH2:43]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC1
Yield: 72.7 %

Procedure:
Following general N—C coupling procedure 1, tert-butyl-3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (119 mg, 0.359 mmol) was combined with 2-chloro-7-cyclobutyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.359 mmol) which gave tert-butyl 3-(6-(7-cyclobutyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (150 mg) in 73% yield. MS m/z 575.2 (M+H)+.