Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[Br-:15].[S:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=S(=O)(c1ccc(CBr)cc1)C(F)(F)F
Solvent: Cc1ccccc1C
Product: O=S(=O)(c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(F)(F)F
Product: [Br-]

Procedure:
A solution of 30.3 g (0.1 mole) of 4-triflyl-alpha-bromotoluene and 28.8 g (0.1 mole) of triphenylphosphine in xylene is heated at reflux for 19 hours. 4-Triflylbenzyltriphenylphosphonium bromide is then isolated by filtration, washed with additional portions of xylene, and dried.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=C1N=CC=N1)=O.[C:20]([NH:23][NH2:24])(=O)[CH3:21].C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:21][C:20]1[O:12][C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[N:24][N:23]=1
Reactant: CC(=O)NN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: BrC(Br)(Br)Br
Agent: O=C=C1N=CC=N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnc(CNC(=O)OC(C)(C)C)o1
Reaction time: 0.5 h
Yield: 107.9 %

Procedure:
To a stirred solution of Boc-Glycine (1.75 g, 10.0 mmol) in CH2Cl2 at 0° C. was added carbonyl imidazole (1.7 g, 10.5 mmol) and the reaction was stirred for 30 min and then acetic hydrazide (740 mg, 10.0 mmol) was added. After 45 min, CBr4 (6.63 g, 20.0 mmol) and PPh3 (5.25 g, 20.0 mmol) were added and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated partially and chromatographed (50% EtOAc in hexanes) to provide 2.3 g of tert-butyl (5-methyl-1,3,4-oxadiazol-2-yl)methylcarbamate with some triphenylphosphine oxide as impurity.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][C@@H:28]1[S:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([C:23]([O:25][CH2:2][C:1]#[N:4])=[O:24])[CH2:26][CH2:27][C@@H:28]1[S:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)OCC#N
Reaction time: 3 h
Yield: 87.2 %

Procedure:
N,N-Diisopropylethylamine (48 μL, 0.276 mmol) and subsequently bromoacetonitrile (88 μL, 1.255 mmol) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-((S)-3-(tert-butoxycarbonyl) thiazolidin-5-yl)butanoic acid (Compound tk2) (98 mg, 0.251 mmol) in acetonitrile (0.5 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 3 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-tert-butyl 5-((S)-3-((tert-butoxycarbonyl)amino)-4-(cyanomethoxy)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk3) (94.0 mg, 87%).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:18]=[C:17]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:16]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C>[CH2:34]([O:33][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:18]=1)[CH2:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[C:8]([CH3:38])[CH:9]=1)[CH:35]([CH3:36])[CH3:37]
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness.
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[CH3:13].N([O-])=O.[Na+].C1(C)C=CC=CC=1.CCCCCC.[BrH:31]>O>[Br:31][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[CH3:13]
Reactant: Br
Reactant: Cc1c(N)c(F)cc(C(=O)O)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1c(F)c(C(=O)O)cc(F)c1Br
Reaction time: 1 h

Procedure:
In 658 ml of 4.7% hydrobromic acid was suspended 26.3 g of 4-amino-2,5-difluoro-3-methylbenzoic acid, and 161 g of cupric bromide was added to the suspension. To this suspension was dropwise added a solution of 16.5 g of sodium nitrite in 165 ml of water over one hour with ice-cooling, and the resulting mixture was stirred for one hour at the same temperature and then at room temperature for two hours. To the reaction mixture was added 700 ml of toluene and the organic layer formed was separated, washed with 100 ml of conc. hydrochloric acid and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. To the residue obtained was added n-hexane and the resulting crystals were collected by filtration to obtain 29.5 g of colorless, crystalline 4-bromo-2,5-difluoro-3-methylbenzoic acid.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:2]3[C:7](=[O:8])[NH:6][C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[S:3]3)[CH2:22][CH2:21]2)=[O:19])=[CH:26][CH:27]=1
Reactant: O=C1Nc2ccccc2SC1Cl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(C2Sc3ccccc3NC2=O)CC1
Yield: 15 %

Procedure:
7 g (=0.035 m) of 2-chloro-2H-1,4-benzothiazine-3(4H)-one, 7.25 g (=0.035 m) of 4-(4-fluorobenzoyl)-piperidine and 7.1 g of triethylamine in 200 ml of toluene were heated at reflux for 4 hours with stirring. The reaction mixture was worked up by cooling it and then adding 200 ml of toluene and 200 ml of water. The pH of the mixture was adjusted to pH 7 by adding 0.1N hydrochloric acid solution. The organic phase was separated, washed with 200 ml of water, and the solvent was distilled off. The title compound was recovered from the remaining oily residue by fractional column chromatography, crystallized from ethyl acetate, and recrystallized in an ethanol/diethyl ether mixture. 1.95 g of 2-[4-(4-fluorobenzoyl)-piperidin-1-yl]-2H-1,4-benzothiazine-3(4H)-one were obtained as a colorless crystalline powder having a melting point of 218° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19]Cl)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21]([OH:25])[CH2:22][CH2:23][OH:24]>>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][O:24][CH2:23][CH2:22][CH2:21][OH:25])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1nn(Cc2ccccc2)c2ccccc12
Reactant: OCCCO
Agent: [Na+]
Agent: [OH-]
Product: OCCCOCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 130 °C

Procedure:
To a solution of NaOH (2.8 g; 0.07 mol) in 1,3-propanediol (150 ml) stirred at room temperature was added 1-benzyl-3-chloromethylindazole, prepared as described in Example 2a of EP 382 276 (17.6 g; 0.07 mol). The solution was heated at 130° C. for 4 hours and then cooled to room temperature, and the solvent was evaporated off under reduced pressure. The residue was taken up in water (100 ml) and the product was extracted with ethyl acetate (3×100 ml). The combined organic phases were concentrated under reduced pressure and the crude residue obtained was purified by flash chromatography on silica gel, using as eluent a 1/1 hexane/ethyl acetate mixture. The product was purified by crystallization from an approximately 1/1 hexane/ethyl acetate mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(CC)CC.[C:22]([C:24]1[C:25]([C:38]([F:41])([F:40])[F:39])=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34](=[NH:37])[NH:35]O)[CH:28]=[CH:27]2)#[N:23]>CC#N>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]1[O:5][N:37]=[C:34]([CH2:33][N:29]2[C:30]3[C:26](=[C:25]([C:38]([F:41])([F:39])[F:40])[C:24]([C:22]#[N:23])=[CH:32][CH:31]=3)[CH:27]=[CH:28]2)[N:35]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)ccc3Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
2-Chloro-5-(trifluoromethyl)benzoyl chloride (0.017 g, 0.071 mmol), Et3N (0.008 g. 0.078 mmol) and 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.020 g, 0.071 mmol) were combined in CH3CN (1.5 mL). After stirring at rt for 1 h, the mixture was heated to 150° C. in a microwave for 10 min. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.025 g): MS (ESI): m/z 469 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:16]=[C:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]1[CH2:27][C:28](O)=[O:29]>>[Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[N:9]=2)=[C:4]([NH:7][C:28](=[O:29])[CH2:27][N:18]2[C:19]3[C:24](=[N:23][CH:22]=[CH:21][CH:20]=3)[CH2:25][CH2:26][C:17]2=[O:16])[S:5][CH:6]=1
Reactant: CC(C)c1n[nH]c(-c2c(Cl)csc2N)n1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: CC(C)c1n[nH]c(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The title compound was prepared from 4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (117 mg, 482 umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (155 mg, 752 umol) using protocol A and was purified by HPLC to yield N-(4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide. Method [7] Retention time 0.35 min by HPLC (M+=431 and 433) and (M+Na=453 and 455). 1H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.30 (d, J=5.1 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.51 (m, 1H), 7.16 (d, J=1.8 Hz, 1H), 4.89 (s, 2H) 3.17 (m, 2H), 2.98 (m, 1H), 2.81 (m, 2H), 1.28 (d, J=7.2 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].O.[F-].C([N+](CC)(CC)CC)C.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.O>CN(C=O)C>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:9][C:6]=1[CH2:7][OH:8])([O-:12])=[O:11]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.3 %

Procedure:
A mixture of 5-hydroxy-2-nitrobenzyl alcohol (5.1 g, 30 mmol), tetraethylammonium fluoride hydrate (8.94 g, 60 mmol) and 2-chloromethylquinoline (5.31 g, 30 mmol) in DMF (90 ml) was stirred at room temperature for 72 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated in vacuo. To the residue was added methylene chloride (25 ml) and the solid was filtered to provide 3.1 g of 2-nitro-5-(2-quinolylmethoxy)benzyl alcohol.
Reaction SMILES: Cl.[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:20]([O:19][C@H:12]1[C@H:13]([NH:18][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:14][C@H:15]([CH2:16][OH:17])[C@H:11]1[O:10][C:2](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoate hydrochloride (150. mg, 0.380 mmol) in DCM (10.0 mL) at 0° C. was treated with Et3N (0.170 mL, 1.22 mmol) and stirred for 20 min. Isonicotinoyl chloride (88.0 mg, 0.490 mmol) was then added and the mixture was stirred for 2 h. The reaction was treated with saturated aqueous solution of ammonium chloride (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (100. mg, 60%). LC/MS: Rt=1.49 min, ES+ 461 (FA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12
Reactant: CS(=O)(=O)OCc1ccccn1
Product: O=C(c1cn(Cc2ccccn2)c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidine] (prepared according to example 8) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound. ES-MS m/e (%): 457.2 (M+H+).
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=S)[CH2:24][O:23][CH2:22]2)[CH:20]=1)([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.[NH3:30].C(OO)(C)(C)C>CO.O>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@:21]2([CH3:28])[CH2:22][O:23][CH2:24][C:25]([NH2:30])=[N:26]2)[CH:20]=1)([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
Reactant: N
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=S)N1
Agent: CC(C)(C)OO
Solvent: O
Solvent: CO
Product: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(N)=N1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A suspension of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thione [Building block H, step b)] (1.25 g, 3.09 mmol) in methanol (57 ml) was treated with a solution of ammonia in methanol (26.5 ml, 185 mmol) and a solution of tert-butyl-hydroperoxide (4.28 ml, 30.9 mmol). After stirring at room temperature for 40 hours, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, evaporated, and dried at high vacuum at room temperature to yield the crude (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine as a light brown foam which was dissolved in dioxane (20 ml) and treated with hydrochloric acid (1 M, 3.09 ml). After 40 minutes at room temperature the reaction mixtures was diluted with a saturated solution of hydrogen-carbonate and water. The mixture was extracted three times with ethyl acetate, then the aqueous phase basified with a solution of sodium hydroxide (28%). After four extractions with dichloromethane, the organic layers were combined, dried over sodium sulfate and evaporated. The (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as an off-white waxy solid (445 mg, 64% of theory).
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH2:11][C:12]([OH:14])=O.[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[CH2:36]([O:35][CH2:34][C@H:16]([NH:15][C:12](=[O:14])[CH2:11][N:3]1[CH2:2][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CN1Cc2ccccc2C1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1Cc2ccccc2C1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(isoindolin-2-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 240, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(isoindolin-2-yl)acetamido)propanamide (11.7 g, 27.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.08 (d, 1H), 7.60 (d, 2H), 7.26 (m, 5H), 7.22 (m, 6H), 7.04-6.98 (m, 4H), 4.75 (m, 1H), 4.52 (s, 2H), 4.00 (s, 4H), 3.73 (m, 2H), 3.42 (s, 2H). MS (EI) for C32H30FN3O4. found 540.6 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COCCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-methoxypropylamine according to general procedure 1 providing the intermediate (43 mg, 54%) as a clear oil: Rf=0.55 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.53 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.95 (quin, J=6.5 Hz, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[O:1]=[S:2]1(=[O:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[CH2:15]/[C:16](/[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=[N:34]\[OH:35])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCS(=O)(=O)CC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCS(=O)(=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-[4-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a light yellow foam, MS (ESI+): m/z=464.2 ([M+H]+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:12].[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([NH:17][C:26]([C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)=[NH:27])[CH:18]=[CH:19][CH:20]=1)[CH3:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOc1cccc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cccc(NC(=N)c2ccc(F)cc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambient temperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.48 g (4.0 mmol) of 4-fluorobenzonitrile in 2.0 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 259.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(C2=CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.142 mmol) in DCM (1 mL) was added TFA (0.35 mL) and the resulting mixture was stirred at room temperature for 2 hr. The reaction was concentrated and dried under the high vacuum to yield 6-(bis(4-chlorophenyl)methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one, which was used in the next step without further purification. (ES, m/z) 461, 463 [M+H]+