Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=O)(O)[OH:2].[NH2:6][C:7]1[NH:11][N:10]=[C:9](S)[N:8]=1.[Cl:13]Cl>Cl>[NH2:6][C:7]1([S:1]([Cl:13])(=[O:5])=[O:2])[N:11]=[N:10][CH:9]=[N:8]1
Reactant: O=S(=O)(O)O
Reactant: Nc1nc(S)n[nH]1
Reactant: ClCl
Agent: Cl
Product: NC1(S(=O)(=O)Cl)N=CN=N1
Temperature: 18 °C

Procedure:
A 1 liter bottom draining glass reactor fitted with a fritted glass gas inlet tube, a gas outlet with a sulfuric acid scrubber, a paddle stirrer, a thermometer, and a jacket connected to a recirculating temperature regulated bath maintained at 18° C. A mixture containing 116 g (1.0 mole) of 5-amino-3-mercapto-1,2,4-triazole and 800 ml of 20 percent aqueous hydrochloric acid (made from 432 ml of 37 percent hydrochloric acid and 368 ml of water) was placed in the reactor and 222 g (3.13 moles) of chlorine was added thorough the gas inlet tube with stirring and cooling over a 165 min period. The temperature of the mixture was maintained at about 22° to about 32° C. under these conditions. The color of the mixture was changeable in the pale yellow to orange range and the initial slurry first thinned out and then became thick again as the reaction proceeded. After all the chlorine was added (uptake and the exotherm ceased), the temperature was reduced to about 5° C. and the mixture was removed though the bottom drain. The solids were collected by filtration, washed with 500 ml of cold water, and air dried to obtain the title compound as a pale yellow solid melting at 169.5°-170° C. (dec.). This amounted to 124 g (68 percent of theory) and was found by HPLC analysis to be about 95.5 percent of the title compound and about 4.5 percent 5-amino-1,2,4-triazole-3-sulfonic acid. The filtrate and wash were found by HPLC analysis to contain additional amounts of the title compound.
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]2[C:14]([CH:15]=[C:16]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17](=[O:27])[O:18]2)=[CH:13][CH:12]=1.ClC(Cl)(Cl)C(=N)O[C@H:43]1[C@@H:48]2[O:49][C:50](=[O:52])[O:51][C@@H:47]2[C@@H:46]([O:53][CH3:54])[C:45]([CH3:56])([CH3:55])[O:44]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:54][O:53][C@H:46]1[C:45]([CH3:56])([CH3:55])[O:44][C@@H:43]([O:10][C:11]2[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:19]3[C:14]([CH:15]=[C:16]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:17](=[O:27])[O:18]3)=[CH:13][CH:12]=2)[C@@H:48]2[O:49][C:50](=[O:52])[O:51][C@H:47]12
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Reactant: O=C(Nc1cc2ccc(O)c(-c3ccccc3)c2oc1=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2-c2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
Boron trifluoride etherate (14.6 μL, 0.12 mmol) was added to 23f (155 mg, 0.39 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (560 mg, 1.55 mmol) in anhydrous CH2Cl2 (9.70 mL). After stirring at room temperature for 48 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 100:1→40:1 CH2Cl2:Acetone) to give 25f as a colorless foam (225 mg, 99%): 1H NMR (CD2Cl2, 400 MHz) δ 8.37 (s, 1H), 7.75-7.73 (m, 2H), 7.60-7.36 (m, 10H), 7.32 (d, J=8.8 Hz, 1H), 5.77 (d, J=1.7 Hz, 1H), 5.26 (s, 2H), 4.76-4.68 (m, 1H), 4.36-4.28 (m, 1H), 3.56 (s, 3H), 3.28 (d, J=7.2 Hz, 1H), 1.37 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.2, 153.0 (2C), 152.1 (2C), 152.1, 134.4, 129.9, 129.8, 129.4, 127.7 (2C), 127.5, 127.2 (2C), 127.1 (2C), 127.0, 126.3, 121.5 (2C), 120.3, 111.2 (2C), 93.9, 81.9, 66.5, 59.4 (3C), 20.9 (2C); IR (film) νmax 3400, 2959, 2926, 2853, 2359, 2341, 1819, 1715, 1601, 1522, 1381, 1366, 1261, 1215, 1173, 1111, 1059, 970, 800, 700 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C32H29NO10, 588.1870. found, 588.1846.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([S:24][CH3:25])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][S:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:21]=[CH:20][C:19]=1[C:22]#[N:23]
Reactant: CSc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1cc(CCN2CCNCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate (440 mg, 1.32 mmol) in 10 mL of DMF was dropped NaSMe (0.66 mL, 1.8 mmol, 21% in water). The mixture was stirred at 70° C. for 3 hours. The reaction was diluted with 40 mL of EtOAc and 40 mL water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to give tert-butyl 4-{2-[4-cyano-3-(methylthio)phenyl]ethyl}piperazine-1-carboxylate (250 mg, 52% yield). MS: m/e 362 (M+1)+. To a solution of tert-butyl4-{2-[4-cyano-3-(methylthio)phenyl]ethyl}piperazine-1-carboxylate (250 mg, 0.69 mmol) in 5 mL of DCM was added 5 mL of TFA was stirred at room temperature for 1 hours, and the reaction was concentrated. The residue was diluted with 30 mL of aq. NaHCO3 and 30 mL of DCM: MeOH (v/v=10/1). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2-(methylthio)-4-(2-piperazin-1-ylethyl)benzonitrile.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.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>ClCCl>[CH:1]1([CH2:7][C@@H:8]([C:9]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:11])[CH2:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: O=C(C[C@@H](CC1CCCCC1)C(=O)O)NCCNc1ccc(F)cc1
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: O=C(C[C@@H](CC1CCCCC1)C(=O)N1CCOCC1)NCCNc1ccc(F)cc1
Yield: 48.1 %

Procedure:
(R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid (220 mg, 0.52 mmol) was treated with morpholine (110 μL, 1.26 mmol, 2.4 eq.) and HATU (238 mg, 0.72 mmol, 1.4 eq.). The reagents were dissolved in dry dichloromethane (4 mL) and treated with diisopropylethylamine (315 μL, 1.81 mmol, 3.5 eq.). The reaction was judged to completion by LC/MS, volatiles were evaporated and the reaction was purified by prep-LC/MS and provided 131 mg (0.25 mmol, 40%) of a off-white solid: HPLC-MS calcd. for C23H34FN3O3 (M+H+) 420.3, found 420.5.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11]C)[C:7]=1Cl.[CH3:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][NH2:27])=[CH:18][CH:17]=1.O.O1CCOC[CH2:30]1>>[Cl:1][C:2]1[C:3](=[O:13])[NH:4][N:5]=[C:6]([O:9][CH:10]([CH3:11])[CH3:30])[C:7]=1[NH:27][CH2:26][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][CH3:14])=[CH:17][CH:18]=1
Reactant: CCCOc1n[nH]c(=O)c(Cl)c1Cl
Reactant: C1COCCO1
Reactant: COc1ccc(CN)c2ccccc12
Solvent: O
Product: COc1ccc(CNc2c(OC(C)C)n[nH]c(=O)c2Cl)c2ccccc12
Reaction time: 3.5 h

Procedure:
A mixture comprising 350 mg of 4,5 dichloro 6-1-propoxy-3(2H)pyridazinone, 1.23 g of 4-methoxy-1-naphthylmethylamine and 30 ml of a mixture of water/1,4-dioxane (volume ratio of 1/1), was refluxed under stirring for 3.5 hours. The reaction mixture was concentrated, and precipitated crystals were collected by filtration and recrystallized from a mixture of methanol/water to obtain 420 mg of the above identified compound as colorless crystals having a melting point of from 244° to 247° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
Diphenylmethyl 3-methoxymethyl-7β-(2'-thienylacetamido)-ceph-3-em-4-carboxylate (2 g.,) was dissolved in a mixture of trifluoroacetic acid (8 ml) and anisole (2 ml) and after 5 minutes the reagents removed under reduced pressure. The resulting gum was dissolved in ethyl acetate and poured into 60°-80° petroleum and the product recovered by filtration. This material crystallised from ethyl acetate as colourless prisms, m.p. 153°-157° (decomp.), [α]D25 + 81.6°(c 1, tetrahydrofuran), λmax (ethanol) 237, 260 (Sh.) nm (ε 13,700 and 7,700 respectively), νmax (Nujol) 1780 (β-latham), 1720 (-COOH), 1690 and 1524 cm-1 (-CONH), N.M.R. 5,80 (-CH2OCH3), 6.70τ (-CH2OCH3), (Found: C, 49.2; H, 4.4; N, 7.5; S, 17.0. C15H16N2O5S2 requires: C, 48.9; H, 4.4; N, 7.6; S, 17.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[N:15][C:14]([CH2:17][OH:18])=[C:13]3[O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22][C:12]=23)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]>O=[Mn]=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([C:11]1[CH:16]=[N:15][C:14]([CH:17]=[O:18])=[C:13]2[O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22][C:12]=12)=[O:10]
Reactant: CC1(C)OCc2c(C(=O)c3ccc(F)c(Cl)c3)cnc(CO)c2O1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC1(C)OCc2c(C(=O)c3ccc(F)c(Cl)c3)cnc(C=O)c2O1

Procedure:
(4-fluorophenyl)(8-(hydroxymethyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanone (total yield from step 1d) was added to 200 mL of CHCl3 and 15 g MnO2. The resulting suspension was refluxed for 4 h to completion. MnO2 was then removed by filtration through CELITE® (a diatomite filter) and washed 2× with CHCl3. Evaporation of the solvent gave 5 g of crude product which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:7]=1)=[O:5])C.[OH-].[Na+]>CO>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2OCC2CCCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)nn1Cc1cc(Cl)ccc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ester 3 (0.086 g, 0.25 mmol) in MeOH (10 mL) was added a solution of 2 M NaOH 2 mL (0.40 mmol) and the resulting mixture was stirred at RT for 4 hours. The volatiles were removed in vacuo. The residue was diluted with water (5 mL) and acidified to pH 1 with 2 M HCl. The acid 4 was isolated by filtration as a white solid and washed with water and dried overnight over KOH in a dessicator to yield 1-(5-chloro-2-cyclopentylmethoxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid, 4, as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][C:26]=3[O:28][CH3:29])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1ccc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)c1
Yield: 59.9 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2,4-dimethoxyphenylboronic acid (175 mg, 0.96 mmol) were reacted. After purification the title compound (110 mg, 60% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J=4.8 Hz, 1H), 8.47 (a dd, J=5.6, 9.3 Hz, 1H), 7.70 (t, J=9.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.70(s, 1H), 6.63 (a d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 3H), 2.95 (m, 1H), 0.67 (m, 4H). MS APCI, m/z=383.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[OH:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([CH:13]=[C:12]([Cl:17])[C:11]=1[O:18][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)[NH2:16]
Reactant: Clc1ccc(Cl)nn1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Nc1cc(Cl)c(Oc2ccc(Cl)nn2)c(Cl)c1

Procedure:
In one embodiment, the process further comprises providing the compound of Formula (I) by contacting 3,6-dichloropyridazine with 2,6-dichloro-4-aminophenol to form 3,5-dichloro-4-((6-chloropyridazin-3-yl)oxy)aniline, hydrolyzing 3,5-dichloro-4-((6-chloropyridazin-3-yl)oxy)aniline and protecting the amine group of 3,5-dichloro-4-((6-chloropyridazin-3-yl)oxy)aniline either before or after the hydrolysis to form the compound of Formula (I). The contacting of 3,6-dichloropyridazine with 2,6-dichloro-4-aminophenol is performed in a polar aprotic solvent (e.g., dimethylacetamide (DMAC)) in the presence of a base (e.g., Cs2CO3) at a reaction temperature between 60 and 120° C. (e.g., about 65° C.). Further, a purification step may be included. That is, before step (a), the compound of Formula (I) is purified in an acidic solution at a temperature between 80 and 100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][O:21][C:15]=3[CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:6].[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:20]1[O:21][C:15]2[CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:22]=[CH:23][C:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[O:2][CH3:1])=[CH:8][CH:9]=3)[CH2:18][CH2:17][C:16]=2[CH:19]=1)[CH3:30]
Reactant: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3cc(CN(C)C)oc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.320 g (0.885 mmol) of 6-[4-(2-methoxybenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.120 ml (1.33 mmol) of 50% aqueous dimethylamine and 0.108 ml (1.33 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: C(/[O-])=C(\[N+]([O-])=O)/C=O.O.[Na+].C(O)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[N:22]1.O>C(O)(=O)C.[Fe]>[Cl:14][C:15]1[CH:16]=[C:17]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]1
Reactant: CC(C(=O)O)c1ccc(-n2cc([N+](=O)[O-])cn2)c(Cl)c1
Agent: [Fe]
Agent: O=C/C(=C\[O-])[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-n2cc(N)cn2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The starting compound is obtained in the following manner: 22.8 g (59 mmoles) of 2-(3-chloro-4-hydraziniumphenyl)propionic acid p-toluenesulphonate and 9.8 g (64 mmoles) of sodium nitromalondialdehyde monohydrate are heated under reflux for 30 minutes in 180 ml of 80% strength ethanol. Concentration is then effected, followed by taking up with sodium bicarbonate and extraction with ether. The aqueous solution is acidified and extracted with ether. Through concentration of the ethereal phase there is obtained, after recrystallisation from ethanol, 2-[3-chloro-4-(4-nitropyrazol-1-yl)phenyl]propionic acid (m.p. 173°-173.5° C.). 5 g (16.9 mmoles) of 2-[3-chloro-4-(4-nitropyrazol-1-yl)phenyl]propionic acid are dissolved in 30 ml of glacial acetic acid, heated to 80° C.; portionwise, 3.8 g of iron powder and then 7 ml of water are added. After one hour, pouring on to ice is effected, followed by extraction with ether. The ether phase is dried, clarified with Tonsil, and concentrated. 2-[3-chloro-4-(4-aminopyrazol-1-yl)phenyl]propionic acid is obtained as oil [RF =0.25 (silica gel; CHCl3 /ethanol 4:1)].
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Li+].C[Si]([N-:17][Si](C)(C)C)(C)C.[OH-].[Na+].CO>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:17]
Reactant: O=C(c1ccccc1)C(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(c1ccccc1)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 2,2-difluoro-1-phenylethanone (1 g, 6.4 mmol) in toluene (32 mL) at room temperature was added LiHMDS (1M in THF) (7.05 mL, 7.05 mmol). The reaction mixture was stirred for 30 min, followed by addition of BH3-DMS (1.216 mL, 12.81 mmol). The reaction mixture was stirred for 1 h. After cooling at 0° C., aqueous 2 N NaOH solution was carefully added over 5 min (Caution! gas evolution). The reaction was stirred for 1 h. The layer was separated and washed with water and brine. After dried over sodium sulfate, HCl in MeOH (7.17 mL, 8.97 mmol) was added to form a white precipitate. The precipitate was filtered off, washed with ether, and dried in vacuo yielding 2,2-difluoro-1-phenylethanamine (21%). 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (s, 5H), 6.52-6.07 (m, 1H), 4.78-4.69 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][CH:6]=[C:5]2[CH:9]=O)[CH2:3][CH2:2]1.[C:11]([O:20][CH2:21][CH3:22])(=O)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.C(O[K])(C)=[O:25]>CCO.C(OC(=O)C)(=O)C>[C:21]([O:20][C:11]1[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[C:5]2[C:6]=1[CH:7]=[CH:8][N:4]2[CH:1]1[CH2:2][CH2:3]1)(=[O:25])[CH3:22]
Reactant: CC(=O)O[K]
Reactant: O=Cc1cccn1C1CC1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(OC(C)=O)c2ccn(C3CC3)c2c1
Temperature: 25 °C

Procedure:
14.57 g of Na was added portionwise to 400 ml of EtOH. To the mixture was added a solution of 38.91 g of 1-cyclopropyl-1H-pyrrole-2-carbaldehyde and 48.23 ml of diethyl succinate in 100 ml of EtOH at 50° C., then the mixture was refluxed overnight. 140 ml of 5N HCl was added to the mixture at 0° C. and EtOH was evaporated. The concentrate was extracted with CHCl3 and the extract was dried over Na2SO4 and concentrated to give red oil. The material was dissolved in 400 ml of acetic anhydride and 47.40 g of AcOK was added thereto. The mixture was refluxed for 30 min and allowed to cool to room temperature. The mixture was filtrated and the filtrate was concentrated. The residue was purified on SiO2 column chromatography (n-hexane-EtOAc system) to give 72.3 g of ethyl 4-acetoxy-1-cyclopropyl-1H-indole-6-carboxylate as red oil.
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:39][C:33]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:37][N:36]([C@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:35][CH2:34]1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(O)(c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.3 %

Procedure:
To a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70 mmol) in THF (25 mL) was added triethylamine (1.31 mL, 9.42 mmol), followed, by tetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) was added. The mixture was stirred for 16 hours and then it was diluted with ethyl acetate (100 mL), washed (H2O×2, brine), dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column (0-60% ethyl acetate-hexane) to provide an approximately 2:1 mixture of diastereomers, as judged by 1H NMR. Separation of these isomers was performed using supercritical fluid chromatography (CHIRALCEL® OJ-H, 30×250 mm; 20% ethanol in CO2 at 35° C.), to give first the (R)-isomer of the title compound (0.534 g, 27%) as a yellow oil and then the corresponding (S)-isomer (0.271 g, 14%), also as a yellow oil. (S,R)-isomer: 1H NMR (400 MHz, CD3OD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m, 10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72 (m, 1H), 2.64 (dt, J=11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt, J=11.1, 2.5 Hz, 1H), 2.20 (dt, J=12.1, 4.6 Hz, 1H), 2.10 (dt, J=12.1, 4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J=6.5 Hz, 3H). LCMS: Anal. Calcd. for C27H29NO3: 415; found: 416 (M+H)+; (S,S)-isomer: 1H NMR (400 MHz, CD3OD) 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H), 7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5 Hz, 1H), 2.57-2.52 (m, 1H), 2.42 (dt, J=11.1, 2.5 Hz, 1H), 2.25 (dt, J=12.1, 4.6 Hz, 1H), 2.12 (dt, J=12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H), 1.64 (dd, J=13.6, 3.0 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). LCMS: Anal. Calcd. for C27H29NO3: 415; found: 416 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32](O)=O)[N:17]=1>>[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[N:19]=[C:18]([C:32]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[N:17]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C(=O)O)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2nc(-c3cccc(S(N)(=O)=O)c3)no2)n1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.74 mmol) and 4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.8) (0.14 g, 0.50 mmol) according to the general procedure V. Obtained as a white solid (0.097 g, 42%). MS (ISP) 462.1 [(M+H)+]; mp 240.5° C.