Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:35](=[O:37])[CH3:36])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)4-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 8, 9.45 g) in dry methylene chloride (96 mL) under N2 is treated with pyridine (5.82 mL) and acetic anhydride (3.40 mL), and the resulting mixture is stirred at ambient temperature for four hours, diluted with methylene chloride (25 mL), washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/chloroform (2.5/97.5-7.5/92.5). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 144-146° C.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][C:32]([O:34]CC)=[O:33])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:1].[C:2]1([N:8]([CH2:31][C:32]([OH:34])=[O:33])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)O)c4ccccc4)ccc3s2)cc1
Yield: 75 %

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 75% of theory, C24H21N5O3S (459.53) Rf value: 0.14 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) ##EQU4##
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
Concentrated sulphuric acid (200 ml) is cooled to 5° C. 4-Fluoroacetophenone (20 ml, 164.76 mmol) is added so that the temperature does not rise above 10° C. The mixture is cooled to 0-5° C. and potassium nitrate (25 g, 247.14 mmol) is added portionwise over 2 hours keeping the temperature at 0-5° C. Following the addition the mixture is stirred at this temperature for 2 hours. The mixture is poured on ice (600 g) and the crude product is filtered off. Column-chromatographic purification on silica-gel using a mixture of ethylacetate and petroleum ether (1:9) as the eluent affords 18.19 g pure 4-fluoro-3-nitroacetophenone (60%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:31]([CH2:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([C:31]1[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:17])([F:16])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:37]
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ncccc1-c1cccc(C2=Nc3cc(C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M214) (312 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (190 mg, 77%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[N:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1.B(Cl)(Cl)Cl>ClC(Cl)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[N:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)nc2)cc1
Agent: ClB(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(OCCN2CCCCC2)nc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C

Procedure:
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][2-[2-(1-piperidinyl)ethoxy]-pyridin-5-yl]methanone (1.8 g, 3.58 mmol) of was dissolved in 20 mL of dichloroethane and 3.1 mL (35.8 mmol) of condensed BCl3 was added. The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for forty-eight hours. The reaction was quenched with 5 mL of MeOH and reaction was stirred for one hour. The reaction volume was evaporated to half the orginal volume and chromatographed on a silica gel column eluted with a linear gradient starting with CHCl3 and ending with CHCl3 -MeOH (9:1) (v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. The crude product was again chromatographed on a silica gel column eluted with CHCl3 -MeOH (19:1). This yielded 540 mg of the title compound as a yellow-orange, amorphous solid.
Reaction SMILES: [NH2:1][CH:2]([CH3:30])[C:3]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[S:7][C:6]1([CH2:24][CH2:25][CH2:26][N:27]=[N+]=[N-])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].Cl.N#N>CO.[Pd]>[NH2:1][CH:2]([CH3:30])[C:3]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[S:7][C:6]1([CH2:24][CH2:25][CH2:26][NH2:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:4]
Reactant: CC(N)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CO
Product: CC(N)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reaction time: 40 h
Yield: 87.4 %

Procedure:
2-Amino-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one (50 mg, 0.116 mmol) was dissolved in 5.0 mL of MeOH. HCl (0.46 ml, 0.464 mmol) was added followed by evacuation/re-vacuation with N2. Pd/C (12 mg, 0.011 mmol) was then added followed by H2 balloon. Following 40 hours at 23° C., the reaction was concentrated in vacuo, affording the product (41 mg, 87%) as a cream/yellow colored foam. MS ESI (+) m/z 405 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ7.68 (m, 1H), 7.53 (m, 2H), 7.42 (t, 2H, J=9 Hz), 7.34 (m, 3H), 4.92 (m, 1H), 3.22 (m, 2H), 3.17 (m, 4H), 2.65 (m, 2H), 2.20 (m, 1H), 1.99 (m, 1H), 1.72 (d, 1.5H, J=8 Hz), 1.66 d, 1.5H, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([F:25])=[CH:18][C:17]=1F.CC(OC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:17]2[CH:18]=[C:19]([F:25])[C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[F:15])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a solution of 2-chloropyridin-4-ol (100 g, 772 mmol) in anhydrous DMF (2 L) was added K2CO3 (128 g, 926 mmol) in one portion at RT. The mixture was stirred for 10 min at RT, and was then treated with 1,2,4-trifluoro-5-nitrobenzene (88 mL, 772 mmol) slowly over 10 min. The internal temp of the reaction mixture was maintained below 24° C. during the addition. The reaction was stirred at RT for 1 h and then it was stopped by adding ice/water (10 L). The mixture was stirred for 2 h and then filtered to remove the solids. The solids were washed with water (5 L), hexanes (3 L) and then dried under vacuum at 50° C. to give 194.7 g of crude material. The solids were treated with MTBE (200 mL), stirred for 2 h, collected by filtration, washed with MTBE (50 mL) and dried under vacuum at 40° C. for 3 h to afford 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (164.6 g, 74.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J=10.2, 7.0 Hz, 1 H), 8.41 (d, J=5.6 Hz, 1 H), 7.90 (dd, J=11.6, 6.7 Hz, 1 H), 7.41 (d, J=2.1 Hz, 1 H), 7.26 (dd, J=5.6, 2.4 Hz, 1 H); MS (ESI): m/z 287.0 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])[N:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1coc(C2CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
To a solution of 2-cyclopropyloxazole-4-carboxylic acid (0.1 g, 0.653 mmol) in dry dichloromethane (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.25 g, 1.3 mmol) and hydroxybenzotriazole (0.175 g, 1.3 mmol) at 0° C. portion wise. N,O-dimethylhydroxylamine (64 mg, 0.653 mmol) was then added followed by triethylamine (0.26 mL, 1.95 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with ethyl acetate and washed with water and brine solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by preparative TLC (25% ethyl acetate in petroleum ether) to afford 2-cyclopropyl-N-methoxy-N-methyloxazole-4-carboxamide (100 mg, 83%). MS (ES+) (M+H) 197.25; LCMS retention time: 2.82 min (Method S).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=O)=[O:6])C>CN(C=O)C.[Pd]>[Cl:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][C:11]=1[Cl:15])[N:16]([OH:18])[C:4](=[O:3])[C:5](=[O:6])[NH:7]2
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n(O)c1=O
Reaction time: 1.5 h
Yield: 87 %

Procedure:
This compound was prepared using an adaptation of the method of Loev, et al., supra. A mixture of ethyl-N-(4,5-dichloro-2-nitro-phenyl)oxamate (0.307 g, 1 mmol) and 0.04 g of 5% Pd-C in 5 mL of DMF was hydrogenated at 45 psi for 1.5 h. The reaction mixture was filtered and the liquid was added to water (18 mL). A white precipitation formed. The mixture was vacuum filtered. The solid was rinsed with water (5×2 mL), and air dried for 1 h to yield 215.14 mg (0.87 mmol) of 6,7-dichloro-N-hydroxy-1,4-dihydroquinoxaline-2,3-dione as a pale yellow solid (87%). The pale yellow solid (215 mg, 0.87 mmol) was dissolved in 4 mL of DMSO with heating. Water (0.8 mL) was added until precipitation appeared. The mixture was heated again to redissolve the precipitate. The yellow solution was cooled down. Pale yellow crystals came out which were collected by vacuum filtration and rinsed with water (5×2 mL) and dried in vacuum to yield 173 mg (0.70 mmol) of 6,7-dichloro-N-hydroxy-1,4-dihydroquinoxaline-2,3-dione as pale yellow crystals. Mp >300° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ 12.244 (br s, 1H, NH), 11.953 (br s, 1H, N-OH), 7.562 (s, 1H, H-8), 7.318 (s, 1H, H-5). HRMS calcd. for C8H4Cl2N2O3, 245.9599; found, 245.9600.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:20]=[C:21]([CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)[CH2:14][CH2:13]1)C(=O)[O-])(C)C.Cl>O1CCOCC1>[CH2:29]([C:21]1[CH:22]=[C:23]2[C:28](=[C:19]([O:18][CH:15]3[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][NH2:5])[CH2:13][CH2:14]3)[CH:20]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1cc(OC2CCN(CCCN(C(=O)[O-])C(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1cc(OC2CCN(CCCN)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
1,1-Dimethylethyl(3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)carbamate (for example, as prepared for Intermediate 31) (493 mg, 1.12 mmol) was treated with a solution of hydrogen chloride in dioxane (4 M, 10 ml), and stirred under nitrogen overnight at room temperature. The mixture was concentrated in vacuo. The residue was dissolved in methanol, and applied to a SCX-2 ion exchange cartridge (10 g) which had been preconditioned with methanol. The cartridge was washed with methanol (100 ml), and then eluted with 10% aqueous 0.88 s.g. ammonia in methanol (100 ml). The relevant basic fractions were concentrated in vacuo to give the title compound (292 mg, 76%). LCMS RT=1.92 min, ES+ve m/z 342 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C:23](=[O:29])[CH2:22]2>O1CCCC1.O>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:23]1([OH:29])[CH:24]2[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]2)[CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (6.7 mL) in tetrahydrofuran (THF) (20 mL) at 0° C. was added n-butyllithium (2.3M in hexanes; 20 mL). The reaction mixture was stirred for 40 minutes and then cooled to -78° C. To this mixture a solution of t-butyl acetate (6.4 mL) in THF (10 mL) was added dropwise and stirring was continued for an additional 15 minutes. Quinuclidin-3-one (5 g) in THF (15 mL) was added to the mixture dropwise and the mixture was allowed to warm to 0° C. over 1 hour. To this solution water (100 mL) was added, the solution was extracted twice with chloroform and the combined extracts were washed once with brine. The resulting solution was dried over MgSO4, filtered, and evaporated in vacuo to give 9.53 g of the subtitle compound as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:40])=[C:18]([CH3:39])[C:19]4[N:20]([C:22]([C:32]5[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[CH:33]=5)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:19]3[C:18]([CH3:39])=[C:17]([CH3:40])[C:16]([N:14]4[CH2:13][CH:11]5[CH:10]([CH2:9][NH:8][CH2:12]5)[CH2:15]4)=[N:21][N:20]3[C:22]=2[C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[CH:33]=2)=[CH:26][CH:27]=1
Reactant: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(-c3ccnc(N)c3)c(-c3ccc(F)cc3)nc2c1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(N2CC3CNCC3C2)nn2c(-c3ccnc(N)c3)c(-c3ccc(F)cc3)nc2c1C

Procedure:
To a solution of 2.30 g (4.3 mmol) of 4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine in 150 mL of methanol are added 4 g (64 mmol) of ammonium formate and 1 g of 10% palladium-on-charcoal containing 50% water. The mixture is stirred at reflux for 2 hours and the solvent is then removed under reduced pressure. The residue is taken up in water and the resulting aqueous phase is basified using aqueous 1N sodium hydroxide. The product is extracted with chloroform, the organic phase is washed with water, dried over sodium sulfate and filtered, and the solvent is evaporated off to give an orange-colored oil. After purification by chromatography on a column of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (87:13:1.3), 1.23 g of a white powder are obtained after crystallization from ether and drying under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5]2.Cl[C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1>>[CH3:23][O:22][C:16]1[N:17]=[C:18]([O:20][CH3:21])[N:19]=[C:14]([CH:5]2[C:4]3[C:8](=[C:9]([F:11])[CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:12])[N:15]=1
Reactant: O=C1Cc2cc(F)cc(F)c2N1
Reactant: COc1nc(Cl)nc(OC)n1
Product: COc1nc(OC)nc(C2C(=O)Nc3c(F)cc(F)cc32)n1

Procedure:
5,7-Difluoro-1,3-dihydro-2H-indol-2-one (1.69 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (2.13 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 93% area (2.82 g, 85% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH2:14])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:35]3[N:36]=[C:37]4[C:43]([C:44](O)=[O:45])=[CH:42][N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:38]4=[N:39][CH:40]=3)=[N:30][N:31]2[CH3:34])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:14][C:44]([C:43]2[C:37]3[C:38](=[N:39][CH:40]=[C:35]([C:29]4[C:28]5[C:32](=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=5)[N:31]([CH3:34])[N:30]=4)[N:36]=3)[N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:42]=2)=[O:45])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)C1
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: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 3-(1-amino-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (crude from step 3, 63 mg, 0.31 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (69 μL, 0.39 mmol), 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.26 mmol), and HATU (110 mg, 0.29 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 60% EtOAc/hexanes to afford 158 mg (94%) of 3-(1-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-azetidine-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.23 (s, 1H), 8.36 (t, J=4.3 Hz, 2H), 8.18 (d, J=9.1 Hz, 1H), 7.52 (s, 1H), 7.24-7.29 (m, 1H), 5.73 (s, 2H), 4.57-4.68 (m, 1H), 4.18 (s, 3H), 3.87-4.08 (m, 3H), 3.79 (dd, J=8.7, 6.0 Hz, 1H), 3.55-3.65 (m, 2H), 2.73 (br. s., 1H), 1.39 (s, 9H), 1.36 (d, J=6.8 Hz, 6H), 0.89-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C@H:14]1[CH2:18][C@@H:17]([C:19](=[O:40])[NH:20][C@@H:21]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:22]([NH:24][C@@H:25]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:26]([NH:28][CH3:29])=[O:27])=[O:23])[N:16](CC)[CH2:15]1)=[O:12].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C@H:14]1[CH2:18][C@@H:17]([C:19](=[O:40])[NH:20][C@@H:21]([C:36]([CH3:38])([CH3:37])[CH3:39])[C:22]([NH:24][C@@H:25]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[C:26]([NH:28][CH3:29])=[O:27])=[O:23])[NH:16][CH2:15]1)=[O:12]
Reactant: CCN1C[C@@H](OC(=O)N2CCc3ccccc3C2)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1C[C@H](OC(=O)N2CCc3ccccc3C2)CN1)C(C)(C)C)C1CCCCC1
Yield: 111.7 %

Procedure:
Compound 30 (0.238 g) is treated with DCM-TFA (3 ml-1.5 ml) at 0° C. for 1 h. The volatiles are evaporated to dryness. Compound 31 (crude, 0.253 g) is obtained as white foam for use in the next step.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[Cl:6][C:7]1[CH:8]=[C:9](CO)[CH:10]=[N:11][C:12]=1[Cl:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N>[Br:5][CH2:1][C:9]1[CH:8]=[C:7]([Cl:6])[C:12]([Cl:13])=[N:11][CH:10]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1cc(CBr)cnc1Cl
Temperature: 25 °C

Procedure:
CBr4 (497 mg, 1.5 mmol, Aldrich) was added portionwise to a solution of (5,6-dichloro-pyridin-3-yl)-methanol (178 mg, 1.0 mmol, TCI-US) and PPh3 (393 mg, 1.5 mmol, Aldrich) in CH3CN (3 mL) with stirring at room temperature. The mixture was stirred at room temperature for 30 min, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 242 (M+1).
Reaction SMILES: [OH-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][C:19]([CH3:21])=[O:20]>C1(C)C=CC=CC=1>[O:3]([C:10]1[CH:11]=[C:12](/[CH:13]=[CH:18]/[C:19](=[O:20])[CH3:21])[CH:15]=[CH:16][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
6.7% w/v aqu. NaOH (12 ml) was added to a solution of 3-phenoxybenzaldehyde (40 g, Aldrich) in acetone (200 ml). The mixture was stirred for 1/2 hour and then poured into 2 M aqu. HCl and extracted with ether/pet.ether (1:1). The extract was washed with satd. aqu. NaCl, dried over MgSO4 and stripped to give the aldol product. The latter was taken up in toluene (100 ml) p-toluenesulphonic acid (1 g) was added and the mixture heated on a steam-bath for 1 hour. The mixture was then cooled, washed with satd. aqu. NaHCO3 and satd. aqu. NaCl. dried over MgSO4, and stripped to give the desired product (39.0 g).