Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([CH3:12])([CH3:11])[C:6](=O)[CH2:7][C:8]#[N:9]>CCO>[C:5]([C:6]1[CH:7]=[C:8]([NH2:9])[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:2]=1)([CH3:12])([CH3:11])[CH3:4]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCn1nc(C(C)(C)C)cc1N
Temperature: 85 °C
Reaction time: 20 h
Yield: 117.3 %

Procedure:
To a solution of Example 99A (10.0 g, 41.3 mmol) in EtOH (85 mL) was added hydrazine hydrate (3.02 mL, 61.9 mmol). The mixture was warmed to reflux (85° C.) and was allowed to stir for 20 hours. The mixture was cooled to ambient temperature then 4,4-dimethyl-3-oxopentanenitrile (7.78 g, 61.9 mmol) was added and the mixture was again warmed to reflux (85° C.) and was allowed to stir for 4 hours then the mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (50 mL) was added slowly. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc) provided the title compound (7.6 g, 36.3 mmol, 88% yield). MS (DCI/NH3) m/z 210 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)CCC.O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]([C:35]4[CH:36]=[CH:37][C:32]([O:31][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:33][CH:34]=4)=[CH:19][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(Cc2ccc(F)cc2)CC1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: O=C(c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1)N1CCN(Cc2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a mixture of (4-(4-fluorobenzyl)piperazin-1-yl)(6-bromopyridin-3-yl)methanone (0.048 g, 0.13 mmol, 1.0 eq), 4-benzyloxyphenylboronic acid (0.040 g, 0.18 mmol, 1.4 eq), potassium phosphate (0.053 g, 0.25 mmol, 1.9 eq), S-Phos (0.006 g, 0.01 mmol, 0.1 eq), and tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.01 mmol, 0.01 eq) was added 1-butanol-water (1.25 mL, 4:1). Following a 5 minute purge of the reaction mixture with argon, the reaction vessel was sealed and heated at 100° C. for 10 hours. The reaction mixture was filtered through Celite®, eluting with 5% MeOH—CH2Cl2 and purified by RP-HPLC to provide Compound 17. 1H nmr (D6-DMSO) δ 8.61 (1H, s), 8.06 (2H, d, J 9.0 Hz), 7.95 (1H, d, J 8.0 Hz), 7.83 (1H, dd, J 8.0, 2.0 Hz), 7.48-7.30 (7H, m), 7.16-7.10 (4H, m), 5.16 (2H, s), 3.61 (2H, m), 3.48 (2H, s), 3.37 (2H, m), 2.38 (4H, m); m/z: 483 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:40])[C:12]([C:35]([O:37]CC)=[O:36])=[CH:13][N:14]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH:29]C(OCC)=O)[CH:22]=1)C1C=CC=CC=1.Br>C(O)(=O)C>[NH2:29][C:23]1[CH:22]=[C:21]([N:14]2[C:15]3[C:10](=[C:9]([OH:8])[C:18]([F:19])=[C:17]([F:20])[CH:16]=3)[C:11](=[O:40])[C:12]([C:35]([OH:37])=[O:36])=[CH:13]2)[C:26]([F:27])=[CH:25][C:24]=1[F:28]
Reactant: CCOC(=O)Nc1cc(-n2cc(C(=O)OCC)c(=O)c3c(OCc4ccccc4)c(F)c(F)cc32)c(F)cc1F
Agent: Br
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3c(O)c(F)c(F)cc32)c(F)cc1F
Yield: 39.4 %

Procedure:
Ethyl 5-benzyloxy-1-(3-ethoxycarbonylamino-4,6-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (500 mg) was added to 5 ml of 48% hydrobromic acid and 5 ml of acetic acid. The solution was heated at reflux overnight. The reaction solution was allowed to cool down and concentrated in vacua, and ethanol was added to the residue. The solid was collected by filtration and washed with diethyl ether to give 130 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:27](I)([CH3:29])[CH3:28].O1CCOCC1>C(OCC)(=O)C.CN(C=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:27]([CH3:29])[CH3:28])=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[N:3]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(Nc2nc(Cl)nc3nc[nH]c23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(Cl)nc21

Procedure:
A mixture comprising 0.87 g (3 mmol) of 2-chloro-6-(4-nitro-phenyl-amino)-purine, 0.15 g (4.5 mmol) of caesium carbonate and 1.8 ml (18 mmol) of isopropyl iodide is stirred in 22 ml of a mixture comprising dioxane:water:DMF in a ratio of 2:1:4 at 100° C. for 48 h. Thereafter, the reaction mixture is diluted with ethyl acetate and the organic phase is washed with water and dried over sodium sulfate. After removal of the solvent, the residue is chromatographed over silica gel (mobile phase: CH2Cl2:methanol=9:1). The crystalline precipitate obtained on concentration is filtered off and dried. 2-Chloro-9-isopropyl-6-(4-nitro-phenyl-amino)-9H-purine is obtained; m.p.>260° C.; FAB-MS: (M+H)+=333; Rf=0.8 (CH2Cl2:methanol=9:1).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7][CH3:8])=[CH:5][S:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:12]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:6]([CH2:7][CH3:8])=[CH:5][S:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1
Reactant: CCc1csc(CCc2ccnc(NC(=O)OC(C)(C)C)c2)c1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1csc(CCc2ccnc(N)c2)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
tert-Butyl N-{4-[2-(3-bromo-4-ethyl-2-thienyl)ethyl]-2-pyridyl}carbamate (1.34 g, 4.04 mmol) dissolved in dichloromethane (40 ml) was added with trifluoroacetic acid (40 ml) at 0° C. and stirred at 0° C. for 3 hours. The reaction solution was concentrated under reduced pressure, neutralized with saturated sodium hydrogencarbonate and extracted with chloroform, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=3:1→1:1→ethyl acetate only) to obtain 524 mg (56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.Br[C:21]1[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[C:18][C:21]4[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (267 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (230 mg, 1 mmol) according to general procedure II. Obtained as a light brown solid (158 mg, 44%). MS (ISP) 427.9 [(M+H)+], 429.9 [(M+2+H)+]; mp 265-266° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH:25]([NH:27][C:28]([CH2:30][NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:29])[CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:21])[CH2:19][CH2:18][CH:17]([N:23]3[CH2:26][CH:25]([NH:27][C:28](=[O:29])[CH2:30][NH:31][C:32](=[O:43])[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=4)[CH2:24]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2(O)CCC(=O)CC2)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of [4-(1-hydroxy-4-oxo-cyclohexyl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]=[O:25])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:26]OS([O-])(=O)=O.C[S+](C)C.[OH-].[Na+]>ClCCl.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]1[CH2:26][O:25]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COS(=O)(=O)[O-]
Reactant: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccccc1C
Agent: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(C3CO3)cccc2c1Nc1ccccc1C
Reaction time: 2.5 h
Yield: 53.9 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)quinoline-8-carbaldehyde (0.5 q, 1.5 mmol) was dissolved in dichloromethane (5 ml) and trimethylsulphonium methylsulphate (0.34 g, 1.8 mmol) and 50% aqueous sodium hydroxide (0.75 ml) added. The mixture was stirred vigorously for 2.5 hours, when a further addition of trimethylsulphonium methylsulphate (0.23 g, 1.2 mmol) and 50% aqueous sodium hydroxide (0.5 ml) was made. After stirring for a further 2 hours the mixture was diluted with water and extracted with dichloromethane. The dried extracts were evaporated to an oil, which was purified by flash chromatography (silica gel, ethyl acetate/chloroform). The product crystallised on trituration with petroleum ether to give 3-butyryl-4-(2-methylphenylamino)-8-oxiranylquinoline (0.28 g, 54%), m.p. 114°-116°.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[CH:27])(=O)=O)=CC=1>C(O)C>[CH2:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:26]#[CH:27]
Reactant: NC1CCCCC1
Reactant: C#CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: C#CCOCCOCCNC1CCCCC1
Yield: 37.1 %

Procedure:
Cyclohexylamine (150 mg, 1.5 mmol, 1 equiv.) and 2-(2-(prop-2-ynyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (s-8) (100 mg, 0.335 mmol, 0.2 equiv.) were dissolved in 1 mL of ethanol. The reaction was allowed to proceed under microwave irradiation at 80° C. for 10 minutes, after which it was concentrated under reduced pressure and chromatographed (Silica Gel, 25 g RediSep pre-packed column, 10% EtOAc:Hexanes→50% EtOAc:Hexanes, followed by EtOAc flush) to give N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)cyclohexanamine (s-10) as a clear oil (28 mg, 37%). IR (thin film) 3253 (w), 2924 (s), 2852 (s), 2113 (w), 1449 (m), 1349 (m), 1263 (w), 1102 (s), 919 (w), 839 (w); 1H NMR (400 MHz, CDCl3) δ 4.19 (d, J=2.4 Hz, 2H), 3.70-3.65 (m, 2H), 3.65-3.60 (m, 2H), 3.59 (t, J=5.4 Hz, 2H), 2.80 (t, J=5.4 Hz, 2H), 2.42 (t, J=2.3 Hz, 1H), 2.40-2.34 (m, 1H), 1.90-1.84 (m, 2H), 1.72-1.69 (m, 2H), 1.64-1.54 (m, 1H), 1.30-1.15 (m, 3H), 1.15-0.99 (m, 2H), 0.92-0.81 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 79.6, 74.6, 70.9, 70.1, 69.0, 58.4, 56.8, 42.3, 33.4, 26.2, 25.1. HRMS (ES+) calc'd for C13H23NO2 (M+H) m/z 226.1762 Found 226.1797.
Reaction SMILES: N[CH2:2][CH2:3]N.[C:5]([CH2:8][C:9](=O)[CH3:10])(=O)[CH3:6]>C(O)C>[CH:3]1[CH:2]=[C:10]2[C:8]([CH:9]=[C:10]3[C:8](=[CH:9]2)[CH:5]=[CH:6][CH:3]=[CH:2]3)=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Product: c1ccc2cc3ccccc3cc2c1
Yield: 129.9 %

Procedure:
Prepared by the method of McCarthy, P. J., et al., J. Am. Chem. Soc., 1955, 77, 5820. 1,2-Diaminoethane (1) (3.0 g, 3.3 mL, 49.9 mmol) was dissolved in ethanol (70 mL) and acetylacetone (2) (10.3 mL, 99.8 mmol) was added in a steady stream over a period of about 10 minutes whilst stirring the reaction mixture. The reaction was refluxed for 3 hours. After cooling, evaporation of the solvent in vacuo left a yellow solid which was purified by the addition of diethyl ether (ca. 100 mL). The desired ligand (3) (7.3 g, 32.4 mmol, 65%) was obtained as an off-white crystalline solid by suction filtration.
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].C(=O)(O)[O-].[Na+].[F:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([NH:29][NH2:30])=[O:28]>C(Cl)(Cl)Cl>[NH2:16][C:5](=[N:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=1[F:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: NNC(=O)c1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1ccccc1F
Yield: 75.1 %

Procedure:
A suspension of 15.2 g (0.058 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 160 ml chloroform was treated with 57.7 ml 1N aqueous sodium hydoxide. 80 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 9.98 g (0.063 mol) 2-fluorobenzoic acid hydrazide in 65 ml chloroform over io night at 50° C. The resulting precipitate was filtered off and dried. A yield of 14.6 g 2-fluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid. MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[C@H:3]1[C:15]([OH:17])=[O:16].CC1(C)[C@@H](/C=C\C(=O)OCCOC)[C@H]1C(O[C@H:35]([CH3:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)=O.O(C1C=C(C(O)C)C=CC=1)C1C=CC=CC=1>>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:11])[Cl:12])[C@H:3]1[C:15]([O:17][C@H:35]([CH3:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: COCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C)c2cccc(Oc3ccccc3)c2)C1(C)C
Agent: CC(O)c1cccc(Oc2ccccc2)c1
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step D of Example 9, 6 g of (IR,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy) -1-propynyl]-cyclopropane-carboxylic acid and 4.1 g of 1-(R) (3-phenoxy-phenyl)-ethanol were reacted to obtain after chromatography and elution with an 8-2 mixture of cyclohexane-ethyl acetate 4.38 g of (R)α-methoxy-3-phenoxy-benzyl (IR, cis) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:11]=[CH:12][N:13]1CCCC1>[Ni].CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[CH:12][NH:13]2
Reactant: O=[N+]([O-])c1cccc(F)c1C=CN1CCCC1
Agent: [Ni]
Solvent: CO
Product: Fc1cccc2[nH]ccc12
Yield: 59.7 %

Procedure:
Raney Nickel (500 mg) was added to a suspension of 1-[2-(2-fluoro-6-nitro-phenyl)vinyl]pyrrolidine (6 g, 25.42 mmol) in methanol (50 mL) and hydrogenated under atmospheric pressure at ambient temperature for 20 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to afford 4-fluoro-1H-indole (2.05 g, 60%) as a brown liquid.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]1[NH:27][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=2[N:26]=1
Reactant: N=C(N)COCCc1cc(F)ccc1F
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cc(F)ccc2F)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2). Off-white solid. MS: m/e=336.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[F:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][CH2:27][CH2:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:22]
Reactant: NCCF
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[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: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCF)ccc21
Yield: 44.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-fluoro-ethyl)-amide (75.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-fluoro-ethylamine (38.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 419+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([CH:10]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][NH:12][C:11]1=[O:23])[CH3:9].I[CH2:25][CH3:26]>O>[CH2:8]([CH:10]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][N:12]([CH2:25][CH3:26])[C:11]1=[O:23])[CH3:9]
Reactant: CCC1C(=O)NCCc2ccc(OC)cc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1C(=O)N(CC)CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Charge NaH (60% dispersion in mineral oil) to 100 ml RBF and wash with hexanes. Charge 10 ml anhydrous DMF and 1-Ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (0.500 g, 2.28 mmol). Stir 10 minutes at room temperature and then charge iodoethane (900 uL, 10 mmol) dropwise with syringe. Allow to stir overnight. Pour reaction into 75 ml water and extract with 3×30 ml EtOAc. Dry combined organic over MgSO4, filter and evaporated to yield 1,3-Diethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one. The crude product was used in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([NH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:5])=[O:4].[OH-].[K+].Cl>C1COCC1>[CH3:1][N:2]([CH3:18])[S:3]([NH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:5])=[O:4]
Reactant: COC(=O)c1ccc(CNS(=O)(=O)N(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)NCc1ccc(C(=O)O)cc1
Temperature: 50 °C

Procedure:
Methyl 4-({[(dimethylamino)sulfonyl]amino}methyl)benzoate (0.25 g, 0.918 mmol) was dissolved in THF (5 ml). Potassium hydroxide (5 ml, 10.00 mmol) was added. The reaction was heated to 50° C. for 3.5 h, until reaction was complete as indicated by LCMS. Hydrochloric acid (5 ml, 2N) was added. The reaction was concentrated under reduced pressure. The resulting material was dissolved in organic solvent DCM/MeOH and washed with brine. The aqueous layer was extracted with DCM/MeOH two times. The combined organic layers were dried over Na2SO4, filtered, and concentrated. 1H NMR (d6-DMSO, 600 MHz) δ 12.88 (s, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.76 (t, J=6.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 4.14 (d, J=6.5 Hz, 2H), 2.59 (s, 6H). MS: cal'd 259 (MH+), exp 259 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([N:21]=[N+:22]=[N-:23])=[O:7]
Reactant: C[C@@H]1C[C@H]1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H]1C(=O)N=[N+]=[N-]
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a 0° C. solution of (1R,2R)-2-methylcyclopropanecarboxylic acid (2.0 g, 20.0 mmol) in anhydrous acetone (100 mL) was added triethylamine (2.87 mL, 20.6 mmol) and ethyl chloroformate (1.96 mL, 20.6 mL). The cold bath was removed and the reaction was allowed to warm to room temperature for 30 min before the addition of sodium azide (1.36 g, 21.00 mmol) in water (20 mL). The reaction was maintained at room temperature for 1 h, then diluted with DCM (300 mL) and water (200 mL). The layers were separated and the organic was washed with water (2×100 mL) and brine (100 mL) then dried over MgSO4 and concentrated to provide (1R,2R)-2-methylcyclopropanecarbonyl azide (1.8 g, 72% yield) which was used directly in the next reaction. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.58 (m, 1H), 1.35-1.42 (m, 1H), 1.28-1.34 (m, 1H), 1.14 (d, J=6.0 Hz, 3H), 0.79-0.87 (m, 1H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([NH:28][NH2:29])=[N:16][C:17]([CH3:27])=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1>C1COCC1>[Br:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:29][N:28]=2)[C:17]([CH3:27])=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(NN)n1
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a solution of triphosgene (225 mg, 0.75 mmol) in anhydrous THF (2.5 mL) at 60° C. was added 3-bromo-4-(4-chlorophenyl)-2-hydrazinyl-6-methylpyridine (80 mg, 0.256 mmol) in small portions over 5 min. The resulting suspension was refluxed for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the THF. Water (5 mL) was added carefully to the remaining solution to destroy the excess triphosgene. The resulting aqueous suspension was stirred at room temperature for 30 min, then filtered. The collected solid was washed with water (5 mL×2), the hexanes, and dried in a 45° C. vacuum oven for 3 h to afford 70 mg (84%) of the title compound as a yellow solid. HPLC/MS: retention time=3.38 min, [M+H]+=338.0.
Reaction SMILES: [C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(N(C)C)=O>[CH2:31]([O:2][C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:3])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C1Nc2ccccc2CCC1NC(CCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (as described in example 6, 13.0 g), sodium bicarbonate (10.0 g), and benzyl bromide (19.0 g) in dimethylacetamide (750 ml) was stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction mixture was filtered and evaporated under high vacuum. Water (150 ml) was added, and the resulting solution extracted with dichloromethane (2×400 ml). The combined extracts were washed with water (100 ml), dried over magnesium sulfate and evaporated under reduced pressure to give the crude benzyl ester. Recrystallization from ethyl acetate gave 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 139°-141°.