Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].[CH:61]([C:63]1[CH:71]=[CH:70][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=1)=O>>[C:67]([C:66]1[CH:70]=[CH:71][C:63]([CH2:61][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[NH:45][CH:44]=2)[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])=[CH:64][CH:65]=1)([OH:69])=[O:68]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)Cc1ccc(C(=O)O)cc1)C(C)C

Procedure:
First, in analogy to the preparation of Intermediate 183, Intermediate 192 was reacted with 4-formylbenzoic acid with borane-pyridine complex to give N-(4-carboxybenzyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide. This compound was then used, in analogy to Intermediate 210, to generate 11 mg (68% of theory) of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([Br:16])[CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([Br:16])[CH3:15])=[CH:10][C:11]=2[N+:17]([O-:19])=[O:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2cc(CC(C)Br)ccc21
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(CC(C)Br)cc([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-acetyl-5-(2-bromopropyl)indoline (153 g) in acetic acid (240 ml) was added fuming nitric acid (120 ml) with stirring under ice cooling over a period of 1 hour, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was poured into ice water slowly, the precipitates were collected by filtration, and dissolved in benzene (1.5 l). The benzene solution was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-isopropyl ether to give 155 g of 1-acetyl-5-(2-bromopropyl)-7-nitroindoline melting at 119°-120° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].C(N(CC)CC)C.[N+:15]([C:18]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])=[CH:26][C:19]=1[O:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O-:17])=[O:16].C>C(Cl)Cl.C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])[CH:28]=[CH:29][C:18]=1[N+:15]([O-:17])=[O:16])[CH3:25]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCC1OCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCC1OCCO1
Temperature: 25 °C

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)amine (1.85 grams; 0.015 mole), triethylamine (5 ml) and methylene chloride (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture was cooled in a dry ice bath to a temperature of -20° C. to -10° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (4.2 grams; 0.01 mole) in methylene chloride (50 ml) was added dropwise with stirring. After the addition was completed the reaction mixture was allowed to warm to room temperature with stirring over a period of about 1 hour. After this time the reaction mixture was transferred to a separatory funnel and washed with water (100 ml) with dilute aqueous sodium bicarbonate (200 ml; 5% concentration) and again with water (100 ml). The washed mixture was then dried by passing it through phase separation paper and was stripped of solvent in a rotary evaporator under reduced pressure leaving a white solid residue. This residue was dissolved in toluene, treated with activated charcoal and filtered. The filtrate was partially stripped of toluene and diluted with hexane to precipitate the desired product N-(1,3-dioxolan-2-yl-methyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as a white crystalline solid melting at 148° to 149.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH:10]2[C:19]#[N:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:11][CH:10]2[CH2:19][NH2:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(C#N)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(CN)C1

Procedure:
In a manner similar to preparation 2, react 1-(3,4-dichlorophenyl)-4-(1,1-dimethylethyl)-2-piperazinecarbonitrile with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)CCC>>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: N#Cc1cccnc1-c1cccnc1
Yield: 84 %

Procedure:
Prepared in 84% yield from 2-chloro-3-cyanopyridine and 3-(tributylstannyl)pyridine according to the procedure described for Example 164A. MS (ESI+) m/z 182.0 (M+H)+; 1H NMR (CDCl3) δ 7.44-7.51 (m, 2H), 8.13 (dd, J=7.8, 1.7 Hz, 1H), 8.27-8.31 (m, 1H), 8.77 (d, J=4.7 Hz, 1H), 8.93 (dd, J=8.9, 1.9 Hz, 1H), 9.19 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>>[OH:1][CH2:2][CH:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cccc(C#Cc2ccccc2)c1
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Product: CC(C)(C)OC(=O)NC(CO)c1cccc(C#Cc2ccccc2)c1

Procedure:
(±)-tert-Butyl 2-hydroxy-1-(3-(phenylethynyl)phenyl)ethylcarbamate was prepared identically to the procedure describing the preparation of (S)-tert-butyl 2-hydroxy-1-(3-(phenylethynyl)phenyl)ethylcarbamate except that an equimolar mixture of (DHQ)2PHAL and (DHQD)2PHAL was used.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][C:47]([N:49]1[CH2:54][CH2:53][N:52]([C:55](=[O:66])[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[C:62]([F:65])([F:64])[F:63])[CH2:51][CH2:50]1)=[O:48].Cl>CN(C=O)C.O>[O:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:45][CH2:46][C:47](=[O:48])[N:49]2[CH2:50][CH2:51][N:52]([C:55](=[O:66])[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:62]([F:63])([F:65])[F:64])[CH2:53][CH2:54]2)=[O:21])=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2nnco2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
DIPEA (80 mg, 0.1 mL, 0.64 mmol) was added drop wise to 4-[1,3,4]Oxadiazol-2-yl-benzoic acid (40 mg, 0.2 mmol) in DMF (2 mL). EDCI (45 mg, 0.24 mmol) and HOBT (32 mg, 0.24 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (70 mg, 0.2 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 10% EtOAc in Hexane as eluent) to afford 30 mg (33% yield) of 4-[1,3,4]oxadiazol-2-yl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 93.4%. 1H NMR (CDCl3): δ 8.5 (s, 1H), 8.2 (d, 2H), 8.0 (d, 2H), 7.8 (m, 3H), 7.3 (m, 2H), 4.2 (m, 2H), 3.8 (m, 5H), 3.4 (m, 1H), 3.2 (m, 3H).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([O:32]C)=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([OH:32])=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(Cl)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 0.34 g (14.2 mmol) LiOH in 20 mL water was added to a solution of 3.38 g (6.76 mmol) of (R)-2-(3-chloro-4-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 30 mL THF and the reaction mixture was stirred for 7 h at RT. The mixture was evaporated down i.vac., diluted with 80 mL water, the aqueous phase was extracted twice with 50 mL diethyl ether, the aqueous phase was acidified with 4 M HCl and stirred for 30 min. The precipitated product was suction filtered, washed with water and dried.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:15]([F:17])[CH2:14]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:22]([O:21][C:19]([NH:18][C:13]1([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:16][CH:15]([F:17])[CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(C2CCN(Cc3ccccc3)C2)CC(F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C2CCNC2)CC(F)C1
Reaction time: 1.5 h

Procedure:
A 145 mg (0.416 mmol) portion of 1-benzyl-3-[3-(tert-butoxycarbonylamino)-1-fluorocyclobutan-3-yl]pyrrolidine (Isomer A) was dissolved in 10 ml of ethanol to which was subsequently added 150 mg of 10% palladium on carbon catalyst. The thus prepared mixture was stirred for 1.5 hours under irradiation of light and under a hydrogen pressure of 3.5 atmospheres. After removal of the catalyst by filtration, the solvent was evaporated under a reduced pressure to give 117 mg (quantitative) of the title compound. The thus obtained compound was used in the following reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:15]([S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH:15]([CH3:16])[CH3:17])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CC(C)S(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
2 g of 4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 4-(isopropylthio)benzonitrile. 900 mg of 4-(isopropythio)benzonitrile was reacted via Procedure T to give 4-(isopropylthio)benzoic acid. 730 mg of 4-(isopropylthio)benzoic acid was reacted via Procedure R to give 4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide. MS (Q1) 415.0 (M)
Reaction SMILES: [N:1]1([C:10](OC(C)(C)C)=O)CCCC2[CH2:7][NH:8][CH2:9][CH:2]12.CC1C=CC(S(O[C:28]2[C:29]3[CH2:39][CH2:38][CH2:37][C:36]4[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=4[C:30]=3[N:31]=[C:32](N)[N:33]=2)(=O)=O)=CC=1>>[N:1]1([C:28]2[C:29]3[CH2:39][CH2:38][CH2:37][C:36]4[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=4[C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:2][CH2:9][NH:8][CH2:7][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Product: c1ccc2c(c1)CCCc1c-2ncnc1N1CCNCC1

Procedure:
The title compound was prepared using the procedure outlined in Example 59D substituting piperazine for t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate, and substituting the product from Example 118C for the product from Example 59C. The product was purified by chromatography on silica gel eluting with NH4OH:MeOH:CHCl3 (0.8:8:92) to provide the title compound. 1H NMR (CD3OD) δ 2.32-2.49 (m, 4H), 2.63-2.70 (m, 2H), 2.94-3.01 (m, 4H), 3.47-3.54 (m, 4H), 7.30-7.35 (m, 1H), 7.39-7.44 (m, 2H), 7.65-7.71 (m, 1H), 8.58-8.61 (m, 1H). MS (M+H)+ m/z 281.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])[CH:5]=1)([O-:3])=[O:2].[C:34]([O:41][CH3:42])(=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl>[CH3:39][O:38][C:36]([CH:35]([C:34]([O:41][CH3:42])=[O:40])[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23])=[O:37]
Reactant: COc1ccc(COC(=O)c2cc([N+](=O)[O-])c3ccccc3c2OS(=O)(=O)C(F)(F)F)cc1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)c1c(C(=O)OCc2ccc(OC)cc2)cc([N+](=O)[O-])c2ccccc12
Temperature: 20 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
A stirred solution of 4 (13.20 g, 27.2 mmol) and dimethyl malonate (5.39 g, 40.8 mmol) in DMF (85 mL) was cooled to -5° C. and treated with powdered K2CO3 (22.53 g, 163 mmol). The mixture was allowed to warm to 20° C. over a 2 h period, and after stirring for a further 12 h at 20° C. was poured slowly into cold stirred 0.5N HCl (1750 mL). The resulting solid was dissolved in CH2Cl2 and the solution was washed twice with water, dried (Na2SO4) and then evaporated to dryness. The residue was crystallised from CH2Cl2 /iPr2O/petroleum ether to give 4-methoxybenzyl 1-[di(methoxycarbonyl)methyl]-4-nitronaphthalene-2-carboxylate (5) (10.66 g, 84%), suitable for further use. A sample recrystallised from MeOH had mp 124-125° C. 1H NMR (CDCl3) δ 8.62 (s, 1H, H-3), 8.45 (d, J=8.6 Hz, 1H, H-5), 8.21 (d, J=8.7 Hz, 1H, H-8), 7.70 (br t, J=7.7 Hz, 1H, H-6), 7.69 (br t, J=7.8 Hz, 1H, H-7), 7.41 (d, J=8.7 Hz, 2H, H-2',6'), 6.94 (d, J=8.7 Hz, 2H, H-3',5'), 6.62 (s, 1H, ArCH), 5.37 (s, 2H, CH2), 3.83 (s, 3H, PhOCH3), 3.69 (s, 6H, 2×CO2CH3). Anal. Calculated for C24H21NO9 : C, 61.6; H, 4.7; N, 3.1%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:34]([O:36][C:37]([C@@:39]1([NH2:44])[CH2:41][C@H:40]1[CH:42]=[CH2:43])=[O:38])[CH3:35].[C:45]([N:52]1[CH2:60][C@H:58]([OH:59])[CH2:57][C@H:53]1[C:54](O)=[O:55])([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>ClCCl>[C:48]([O:47][C:45]([N:52]1[CH2:60][C@H:58]([OH:59])[CH2:57][C@H:53]1[C:54](=[O:55])[NH:44][C@@:39]1([C:37]([O:36][CH2:34][CH3:35])=[O:38])[CH2:41][C@@H:40]1[CH:42]=[CH2:43])=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC

Procedure:
A solution of HATU (6 g), diisopropylethylamine (6.8 mL), (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (1.5 g) and BOC-L-hydroxyproline (1.6 g) in dichloromethane was stirred for 1 hrs. The mixture was extracted with DCM-NaHCO3 (aq) dried and concentrated. HPLC purity ca 90% M+H+369.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([CH2:10][CH3:11])=[C:4]([NH2:12])[C:3]=1[CH2:13][CH3:14].CC(C)([O-])C.[K+].[H][H]>[Ru].C(O)(C)(C)C>[NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][CH:5]([CH2:10][CH3:11])[CH:4]([NH2:12])[CH:3]1[CH2:13][CH3:14]
Reactant: CCc1cc(CC)c(N)c(CC)c1N
Reactant: [H][H]
Agent: [Ru]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCC1CC(CC)C(N)C(CC)C1N
Yield: 65.9 %

Procedure:
A suitable autoclave was charged with 1 g (0.052 mol) of purified 1,3-diamino-2,4,6-triethylbenzene, 0.15 g (1.2 mmol) of potassium t-butoxide, 1.0 g of 5% Ru on alumina, and 50 mL of t-butanol and heated to 190° C. at 25.5 MPa hydrogen for 17 hours. The autoclave was then cooled and its contents filtered. The solvent was removed from the filtrate in vacuo and the resulting liquid distilled through a 20.3 cm. Vigreaux column at about 1 mm Hg/187°-191° C. to give 6.8 g (66%) of 1,3-diamino-2,4,6-triethylcyclohexane.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.C(=N[OH:56])C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:56])[NH2:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C#N)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: CC=NO
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C(N)=O)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 110 °C

Procedure:
To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.2 mmol, see Ex. 14) in toluene (10 mL) was added acetaldehyde oxime (240 mg, 4 mmol) and InCl3 (44 mg, 0.2 mmol). The reaction was heated to 110° C. for 3 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:30])[CH2:17]/[CH:18]=[CH:19]/[C:20]1[C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:30][N:16]([CH3:15])[CH2:17]/[CH:18]=[CH:19]/[C:20]1[C:25]([O:26][CH2:27][CH2:28][O:29][C:2]2[C:7]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CN(C)C/C=C/c1ncccc1OCCO
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1/C=C/CN(C)C
Yield: 5.5 %

Procedure:
The procedure in Example 18, Step 4, was followed starting from 2-chloro-3-[(2R)-2-methylpiperazin-1-yl]pyrazine* (0.30 g, 1.4 mmol) and 2-({2-[(1E)-3-(dimethylamino)prop-1-enyl]pyridin-3-yl}oxy)ethanol (from Step 2; 0.32 g, 1.5 mmol). The crude product was purified on a column of silica (100 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (80:20:0.5; 200 mL, followed by 60:40:1) as eluent to give 0.030 g (5.5%) of the title compound as a light brown oil. HRMS m/z calcd for C21H30N6O2 (M)+ 398.2430. found 398.2433. *Reported in WO 00/76984, Example 192, Step 2.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([F:27])[CH:21]=1)[C:14]([O:16]CC)=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.CO>[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([F:27])[CH:21]=1)[C:14]([OH:16])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1ccc(Cl)c(F)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Cl)c(F)c1)C(=O)O
Reaction time: 8 h
Yield: 100.5 %

Procedure:
A solution of Boc2O (1.3 g, 6.1 mmol) and ethyl 3-amino-2-(4-chloro-3-fluorobenzyl)propanoate (1.6 g, 6.1 mmol) in DCM (10 mL) was stirred overnight. The mixture was concentrated in vacuo and chromatographed (SiO2) using DCM as eluent to give ethyl 3-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorobenzyl)propanoate. LiOH—H2O (0.26 g, 6.1 mmol) in H2O (7 mL) was added to a solution of ethyl 3-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorobenzyl)propanoate (0.55 g, 1.5 mmol) in THF/MeOH (7/7 mL) and stirred overnight. The mixture was concentrated in vacuo, acidified to a pH of 1 with 1.0N HCl, and extracted with DCM. The DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using 10% MeOH/DCM as eluent to give 3-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorobenzyl)propanoic acid (0.5 g). LCMS (APCI+) [M-Boc+H]+232.0; Rf: 2.09 min.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[CH:6]=[CH:5][C:4]=2[N:3]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc3nsnc3c2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2nsnc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of 0,4 g (1,8 mmol) 7,8-dihydroxy-1,2,5-thiadiazolo(3,4-f)quinoxaline in 20 ml concentrated sulfuric acid was added at 0° C. 0,19 g (1,9 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min. and at 25° C. for 24 h. The reaction mixture was poured into 100 ml ice-water to give 0,34 g (71%) 7,8-dihydroxy-4-nitro-1,2,5-thiadiazolo(3,4-f)quinoxaline as a precipitate, m.p.>300° C. NMR (DMSO-d6): 12,3 (lH, broad s), 11.6 (lH, broad s), 8.43 (lH,s).