Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccc(F)cc1
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′ ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].CCN(CC)CC.[Br:24][CH2:25][C:26](Br)=[O:27]>ClCCCl.O>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[NH:15][C:26](=[O:27])[CH2:25][Br:24]
Reactant: O=C(Br)CBr
Reactant: Cc1ccccc1C(N)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccccc1C(NC(=O)CBr)c1ccccc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 117.8 %

Procedure:
The compound of Example 554F (100 mg, 0.47 mmol) was dissolved in 2 mL of 1,2-dichloroethane. To this solution at −78° C. was added Et3N (0.05 mL) and then dropwise bromoacetyl bromide (40 mL, 0.47 mmol in 1 mL of 1,2-dichloroethane). The reaction mixture was stirred at −78° C. for 10 min, then at r.t. for 2 h., diluted with water (10 mL), and extracted with 1,2-dichloroethane (2×25 mL). The combined organic layers were concentrated to give the bromoacetamide as a white solid (184 mg, 96%) suitable for further use without additional purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:8]
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: CCCCC(CC)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)CNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-ethyl n-hexylamine (0.37 ml, 0.003 mole) was taken in dry DMSO(40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl-n-hexyl)-(2-(naphthalen-2-yloxy)ethyl]amine, solid, m.p. 92° C., (yield 0.62 gm, 83.6%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH:11]1[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[CH3:33]O>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:1]1[C:9]2[C:4](=[C:5]([O:29][CH2:28][C@@H:27]([OH:32])[CH2:33][N:24]3[CH2:23][CH2:22][N:21]([CH2:20][CH:11]4[O:10][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=5[O:13][CH2:12]4)[CH2:26][CH2:25]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CO
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(CC2COc3ccccc3O2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H)indole and 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=423 (M+ of free base). α[D]589 =-10.21 (c=0.82, methanol).
Reaction SMILES: [CH2:1]=O.[CH2:3]([CH2:5][NH2:6])[OH:4].C([O:10][P:11]([O-:16])[O:12]C(C)C)(C)C>C(O)(C)C>[OH:4][CH2:3][CH2:5][NH:6][CH2:1][P:11](=[O:16])([OH:12])[OH:10]
Reactant: NCCO
Reactant: C=O
Reactant: CC(C)OP([O-])OC(C)C
Solvent: CC(C)O
Product: O=P(O)(O)CNCCO
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of paraformaldehyde (4.0 g, 0.13 mol), ethanolamine (6 mL, 0.097 mol), diisopropylphosphite (17 g, 0.1 mol) and 50 ml of isopropanol was stirred at 120° C. for 16 hours. The solution was concentrated to dryness and 17 ml of 50% NaOH was added. The solution was heated at reflux for 16 h, cooled to room temperature and concentrated under vacuum. Water (100 mL) was added to homogenize the mixture. The reaction was analyzed by 31P NMR in D2O at pH=0.8. N-(2-Hydroxylethyl)aminomethylphosphonic acid was obtained in 33% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)O[C:4](=[O:18])[CH2:3]1.C(N(CC)CC)C.[NH:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH2:27]>ClCCl>[CH2:31]([O:30][C:28]([NH:26][N:27]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[CH:7][CH:2]([CH3:1])[CH2:3][C:4]1=[O:18])=[O:29])[CH3:32]
Reactant: CCOC(=O)NN
Reactant: CC1C=C(c2cccc(C(F)(F)F)c2)OC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NN1C(=O)CC(C)C=C1c1cccc(C(F)(F)F)c1

Procedure:
A solution of 4 g (16 mmol) of 3,4-dihydro-4-methyl-6-(3'-trifluoromethylphenyl)-2-(1H)-pyrone in 100 ml dichloromethane is treated with 5.6 ml of triethylamine and 7.31 g (70 mmol) of ethyl hydrazinoformate, and the mixture is refluxed for 8 hours. After cooling, the reaction solution is washed alternately with distilled H2O, dilute HCl and distilled H2O, dried over Na2SO4 and concentrated on a rotary evaporator. The oil which remains is taken up in 150 ml of toluene, the solution is treated with a spatula-tip full of PTSA and the mixture is refluxed on a water separator until the reaction is complete. For working-up, the reaction solution is washed first with dilute K2CO3 solution and then with distilled H2O and subsequently dried over Na2SO4. The oil obtained after the solvent has been evaporated in vacuo is purified by column chromatography on silica gel (eluent: toluene:acetone=95:5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.C([Li])CCC.[I:17]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([I:17])[S:8][C:7]=2[CH:11]=1
Reactant: II
Reactant: COc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(I)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (5.00 g, 30.49 mmol) in 200 mL of anhydrous THF at -78° C., was added n-butyllithium (20.0 mL, 32.01 mmol, 1.6M solution in hexanes). After stirring for 15 minutes, a solution of I2 (8.10 g, 32.01 mmol) in 25 mL of anhydrous THF was introduced dropwise via canula. The resulting mixture was allowed to gradually warm to ambient temperature. The reaction was quenched by distributing between ethyl acetate/brine (150 mL each). The layers were separated and the organic layer was dried over sodium sulfate. Concentration in vacuo produced a tan solid that was recrystallized from hexanes to provide 6.70 g (75%) of 6-methoxy-2-iodobenzo[b]thiophene. mp 75°-77° C. 1H NMR (CDCl3) d 7.59 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=2.0 Hz, 1H), 6.92 (dd, J=8.6, 2.0 Hz, 1H), 3.86 (s, 3H). FD mass spec: 290. Anal. Calcd. for C9H7OSI: C, 37.26; H, 2.43. Found: C, 37.55; H, 2.43.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([NH2:19])[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[ClH:36].[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([NH:19][S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc(NCCN2CCOCC2)c2occc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=S(=O)(Nc1cc(NCCN2CCOCC2)c2occc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of N7-(2-Morpholin-4-ylethyl)-1-benzofuran-5,7-diamine (58 mg, 0.221 mmol; Intermediate 28) in dichloromethane (2 mL) were added triethylamine (62 μL, 0.442 mmol) and benzenesulfonyl chloride (39 mg, 0.221 mmol). The mixture was stirred at room temperature for 1 h and evaporated. The residue was purified by preparative HPLC (System D), evaporated pure fractions, and converted the resulting TFA salt to a HCl salt. Yield: 32%, HPLC purity=100%, m/z=402 (M+H)+, 1H NMR (270 MHz, methanol-d4) δ ppm 3.43 (t, J=6.06 Hz, 2H) 3.40-3.61 (m, J=6.06, 6.06 Hz, 4H) 3.68 (t, J=6.06 Hz, 2H) 3.75-4.14 (m, 4H) 6.48-6.55 (m, 2H) 6.64 (d, J=2.23 Hz, 1H) 7.41-7.59 (m, 3H) 7.65-7.74 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C@H:19]1[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[C@H:19]1[O:24][CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(C(F)(F)F)cn3)cc2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1cc(Nc2ncc(C(F)(F)F)cn2)ccc1[C@@H]1CNCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.7 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (300 mg) in acetonitrile (2 ml) and water (6 ml) was added trifluoroacetic acid (522 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 16 h. The reaction mixture was then cooled to room temperature and poured into 4 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, CH2Cl2/MeOH/aq. NH3) to afford (R)—N-(3-fluoro-4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine (171 mg, 74%) as an off-white solid. MS (ISP): 343.1 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[NH2:13][CH2:14][CH:15]([OH:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:13]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: CC(O)CN
Product: CC(O)CN1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and 1-amino-2-propanol (Aldrich Cat No. 110248). LCMS (M+H)+=270.0/272.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:7]=[C:6]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: C1CCNC1
Reactant: Clc1cc(N2CCNCC2)nc(Cl)n1
Product: Clc1nc(N2CCCC2)cc(N2CCNCC2)n1

Procedure:
After adding 2.00 g (3.81 mmoles) of 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(2,4-dichloro-6-pyrimidinyl)piperazine in small portions to 20 ml of pyrrolidine at a temperature below 10° C., the reaction mixture is stirred at room temperature for 1 hour, then evaporated. After distributing the evaporation residue between 40 ml of chloroform and 10 ml of 1% sodium hydroxide solution the organic phase is separated, dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column. By using a 99:1 mixture of chloroform and methanol the less polar 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(4-chloro-2-pyrrolidino-6-pyrimidinyl)piperazine is first eluted from the column, which is recrystallized from a mixture of ether and hexane to give a yield of 2.01 g (88.2%), m.p.: 210°-220° C. By further elution the more polar 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(2-chloro-4-pyrrolidino-6-pyrimidinyl)piperazine is obtained which is similarly recrystallized from a mixture of ether and hexane to give a yield of 0.13 g (5.7%), m.p.: 169°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([C:18]#N)=[N:16]2)=[CH:11][CH:10]=1.[OH-:20].[Na+].Cl.[OH2:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([C:18]([OH:23])=[O:20])=[N:16]2)=[CH:11][CH:10]=1
Reactant: O
Reactant: [OH-]
Reactant: COc1ccccc1-c1ccc2cnc(C#N)nn12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1ccc2cnc(C(=O)O)nn12
Yield: 89 %

Procedure:
7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (151 mg, 0.603 mmol) and 9.5 M of Sodium hydroxide in Water (0.20 mL, 1.9 mmol) were combined in Ethanol (6.0 mL) in a vial, which was then heated to reflux for 90 min. The mixture was removed from the heat and treated with 3.00 M of Hydrogen Chloride in Water (1.00 mL, 3.0 mmol), generating a precipitate, which was diluted with water (2 mL), stirred vigorously (thick suspension) then collected by filtration, washing with water (2×8 mL) and drying on the Buchner then in vacuo to afford 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carboxylic acid (145 mg, 89%). LCMS (HPLC): 0.76 min, m/z=270 (M+H); 1H-NMR (DMSO-d6): 13.55 (br s, 1H), 9.27 (s, 1H), 7.73 (d, 1H, J=7.5 Hz), 7.49 (m, 1H), 7.39 (d, 1H, J=4.6 Hz), 7.25 (s, 1H), 7.23 (d, 1H, J=4.6 Hz), 7.12 (m, 1H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3](OC)=[O:4].C[O-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].Cl>CCOCC>[Cl:7][CH:2]([Cl:1])[C:3](=[O:4])[CH2:21][C:20]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([F:11])[CH:13]=1)=[O:22]
Reactant: COC(=O)C(Cl)Cl
Reactant: COc1ccc(C(C)=O)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(C(=O)CC(=O)C(Cl)Cl)cc1F

Procedure:
Methyl dichloroacetate (1.57 g, 11 mmol) was dissolved ether (25 mL). To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol) followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (1.68 g, 10 mmol). After stirring 10 hours 1N HCl (25 mL) was added. The organic layer was collected and washed with water (2×25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude dione was used in the next step without further purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18]([CH3:20])=O)[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(C(F)F)o2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccc(C(F)F)o1

Procedure:
From 2-amino-4-(5-difluoromethyl-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 374 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[Br:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[Br:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-bromo-3-oxo-3-ethoxy-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-70.5°±2° (c=0.7% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.N[CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]1>>[CH:8]([CH:4]1[O:3][C:2]([NH:1][CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[N:6][C:5]1=[O:7])([CH3:10])[CH3:9]
Reactant: CC(C)C1OC(N)=NC1=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC(C)C1OC(NC2CC(C)(C)NC(C)(C)C2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and 4-amino-2,2,6,6-tetramethylpiperidine according to Method G+H.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][C:15]([F:19])=[CH:14]3)[CH2:6][CH2:5]1)(=O)C.[ClH:27]>>[ClH:27].[F:19][C:15]1[CH:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[N:12][N:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]=2[CH:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCC(c2c3ccc(F)cc3nn2Cc2ccccc2)CC1
Agent: Cl
Product: Fc1ccc2c(C3CCNCC3)n(Cc3ccccc3)nc2c1
Reaction time: 6 h
Yield: 25.1 %

Procedure:
A mixture of 8 parts of 1-acetyl-4-[6-fluoro-2-(phenylmethyl)-2H-indazol-3-yl]-piperidine and 70 parts of a hydrochloric acid solution 6N was stirred for 6 hours at reflux temperature. The reaction mixture was evaporated and the oily residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2 parts (25.1%) of 6-fluoro-2-(phenylmethyl)-3-(4-piperidinyl)-2H-indazole monohydrochloride; mp. >300° C. (int. 2).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH2:8])=[O:7])[CH2:3]1.C(Cl)(=O)[C:11](Cl)=[O:12].[CH3:16][N:17]1[CH:21]=[C:20]([C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=3)[CH:23]=2)[CH:19]=[N:18]1.N1C=CC=CC=1>O1CCOCC1.C(Cl)Cl>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH:8][C:11](=[O:12])[NH:35][C:32]2[CH:31]=[CH:30][C:29]([O:28][C:24]3[CH:23]=[C:22]([C:20]4[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=4)[N:27]=[CH:26][N:25]=3)=[CH:34][N:33]=2)=[O:7])[CH2:3]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ncn2)cn1
Reactant: CC1(C)CC(C(N)=O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C4CC(C)(C)C4)nc3)ncn2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of Example B1 (0.120 g, 0.944 mmol) in dioxane (10 mL) was treated with oxalyl chloride (0.120 g, 0.945 mmol), heated at 100° C. for 3 h, concentrated to dryness, dissolved in DCM (10 mL), added to a solution of 5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.120 g, 0.447 mmol) in DCM (10 mL) and pyridine (0.070 g, 0.885 mmol) and stirred at RT overnight. The mixture was concentrated to dryness treated with MeCN and the solid collected via filtration and dried to afford 3,3-dimethyl-N-((5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclobutanecarboxamide (95 mg, 49%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 10.71 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.26 (d, J=2.8 Hz, 1H), 8.16 (s, 1H), 8.05 (d, J=9.0 Hz, 1H), 7.75 (dd, J=9.0, 2.8 Hz, 1H), 7.43 (s, 1H), 3.89 (s, 3H), 3.30 (m, 1H), 2.00 (m, 4H), 1.13 (s, 3H), 1.05 (s, 3H); MS (ESI) m/z: 422.2 (M+H+).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:20]([S:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1)[CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:7])(C)(C)C.C(N(CC)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([CH:20]([S:28][C:29]3[NH:30][N:31]=[N:32][N:33]=3)[CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[OH:19]
Reactant: CCN(CC)c1ccccc1
Reactant: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Solvent: ClCCl
Product: CO[C@@]1(NC(=O)[C@H](O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.04 g (2 mmol) of 7β-amino-7α-methoxy-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g (2 mmol) of N,N-diethylaniline in 100 ml of dry methylene chloride is stirred at 0°-5° while 0.56 g (2 mmol) of D-O-dichloroacetylmandeloyl chloride in 10 ml of methylene chloride is added dropwise over 10 minutes. The mixture is stirred in the cold for 30 minutes when warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml of cold dilute hydrochloric acid and 50 ml of cold 5% aqueous sodium bicarbonate, dried and evaporated to dryness. The residue is dissolved in a mixture of 10 ml of trifluoroacetic acid and 2 ml of m-dimethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml of ether and 50 ml of water and adjusted to pH 9.3-9.5 with 5% aqueous sodium carbonate. The organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, extracted with 50 ml of ethyl acetate which is discarded, layered with fresh ethyl acetate and adjusted to pH 1.5 with dilute hydrochloric acid. The aqueous layer is extracted with three 50 ml portions of ethyl acetate and the combined extracts are dried and evaporated to a small volume. Petroleum ether is added dropwise to precipitate the title compound which is collected by filtration and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Clc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c(Cl)c1
Yield: 48.9 %

Procedure:
Using the procedure of example 1, 2,4-dichloroaniline (131 mg) was reacted with compound 1f (100 mg) to provide compound 36 (47 mg, 49%). 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J=8.0 Hz, 1H), 8.33 (d, J=4.8 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.23 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=5.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0 Hz, 4.8 Hz, 1H). MS (ESI) m/z: 356 (M+H)+.