Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.[CH3:29][N:30]([CH3:38])/[N:31]=[C:32](\[CH3:37])/[C:33]([F:36])([F:35])[F:34].[Br:39][C:40]1[CH:41]=[C:42](/[C:47](=[N:50]\[S@@:51]([C:53]([CH3:56])([CH3:55])[CH3:54])=[O:52])/[CH2:48][F:49])[C:43]([F:46])=[N:44][CH:45]=1>C1COCC1.C1(C)C=CC=CC=1>[Br:39][C:40]1[CH:41]=[C:42]([C@@:47]([NH:50][S@@:51]([C:53]([CH3:56])([CH3:55])[CH3:54])=[O:52])([CH2:37]/[C:32](=[N:31]/[N:30]([CH3:38])[CH3:29])/[C:33]([F:36])([F:35])[F:34])[CH2:48][F:49])[C:43]([F:46])=[N:44][CH:45]=1
Reactant: CC(C)(C)[S@@](=O)/N=C(/CF)c1cc(Br)cnc1F
Reactant: C/C(=N\N(C)C)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)/N=C(/C[C@](CF)(N[S@](=O)C(C)(C)C)c1cc(Br)cnc1F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
Lithium diisopropylamide, 2.0M solution in tetrahydrofuran/heptane/ethylbenzene (1.474 ml, 2.95 mmol) was added dropwise via syringe to a solution of (E)-1,1-dimethyl-2-(1,1,1-trifluoropropan-2-ylidene)hydrazine (0.454 g, 2.95 mmol) in THF 4.0 mL at −78° C. After stirring at −78° C. for 1 h, the solution was added dropwise via cannula to a solution of (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (0.500 g, 1.474 mmol) in toluene 4 mL cooled to −78° C. The reaction was stirred 3 h at −78° C. before being quenched with saturated aqueous ammonium chloride at −78° C. The mixture was warmed up to room temperature and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 10-50% EtOAC/Hexane to give 0.50 g of (R)-N-((S,Z)-2-(5-bromo-2-fluoropyridin-3-yl)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoropentan-2-yl)-2-methylpropane-2-sulfinamide (0.50 g, 1.014 mmol, 68.8% yield). MS m/z=494.9 [M+H]+. Calculated for C16H22BrF5N4OS: 493.3.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:22]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:22]([C:25]1[CH:29]=[C:28]([C:30]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1
Yield: 73.3 %

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (381 mg, 1.3 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.3 mmol), HOBt (210 mg, 1.55 mmol), DIPEA (0.271 mL, 1.55 mmol) and EDCI (298 mg, 1.55 mmol) using DCM as solvent using the method of Example 34(d) affording 410 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 2.47 (s, 3H), 3.63 (m, 2H), 4.69 (m, 1H), 7.03 (d, 1H), 7.25 (bs, 1H), 7.90 (d, 1H), 8.18 (m, 2H), 8.27 (m, 1H), 14.15 (bs, 1H).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C:8]([O:10][C@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:23]=1)[CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=1[Cl:21])=[O:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([CH2:7][C:8]([O:10][C@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH:23]=1)[CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=1[Cl:21])=[O:9])([OH:37])=[O:5]
Reactant: CC(C)(C)OC(=O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
(S)-4-(2-(3-tert-butoxy-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (1.0561 g, 1.878 mmol) was dissolved in DCM (70 ml) and cooled to 0° C. TFA (1.447 ml, 18.78 mmol) was added slowly, and the reaction was stirred at RT for 3 days. Two more additions of TFA (0.723 ml, 9.39 mmol) were performed, and the stirring was continued overnight. The mixture was evaporated to dryness affording (S)-4-(2-(2-carboxyacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.950 g, 1.876 mmol, 100% yield, MS/ESI+ 505.9 [MH]+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:21])[C:12]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=3[F:20])[C:6]=2[CH:5]=[CH:4][N:3]1[CH2:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:25]=2[N:24]=1.[CH3:35][NH2:36].C(O)C>>[CH3:35][NH:36][C:32]([C:30]1[CH:29]=[CH:28][C:26]2[NH:27][C:23]([CH2:22][N:3]3[CH:4]=[CH:5][C:6]4[C:10]([C:11](=[O:21])[C:12]5[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=5[F:20])=[CH:9][NH:8][C:7]=4[C:2]3=[O:1])=[N:24][C:25]=2[CH:31]=1)=[O:33]
Reactant: O=C(O)c1ccc2[nH]c(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1ccc2[nH]c(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1

Procedure:
Following the procedure for example 24, the product obtained in Example 26 was treated with methylamine/ethanol instead of ethylamine to give the titled compound. LC/MS: m/z 480(M+H). 1H-NMR (500 MHz, d6-DMSO). δ 2.78 (d, 3H), 5.55 (s, 2H), 7.04 (d, 1H), 7.35 (t, 2H), 7.58-7.62 (m, 2H), 7.75 (dd, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.44 (d, 1H), 13.1 (d, 1H).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:4]1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[CH2:31][CH3:32]>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:19]2[CH2:18][CH2:17][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=4)[CH2:6]3)[CH2:21][CH2:20]2)=[CH:25][C:24]=1[CH2:31][CH3:32]
Reactant: O=C(O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: CCc1cc(C=O)ccc1Cl
Agent: Cl
Product: CCc1cc(CN2CCC3(CC2)CN(c2ccc(C(=O)O)cc2)C(=O)O3)ccc1Cl
Yield: 43.7 %

Procedure:
The title compound was prepared from 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid hydrochloride salt (20 mg, 0.064 mmol; Example 5-1, Step 4) and 4-chloro-3-ethylbenzaldehyde (11.86 mg, 0.070 mmol), following essentially the same procedure described in Example 7-1. The residue was purified by reverse phase (C-18) HPLC eluting with acetonitrile/water+0.1% NH3. The solvent was evaporated to provide the title compound as a white solid (12 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH:11]1([C@@:14]2([OH:22])[C@H:18]([CH2:19][CH3:20])[NH:17][C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[Cl:10][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:21])[CH2:15][C@:14]([CH:11]3[CH2:13][CH2:12]3)([OH:22])[C@@H:18]2[CH2:19][CH3:20])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C[C@@]1(O)C1CC1

Procedure:
Using 4-bromo-2-chlorobenzonitrile (389 mg), (4R,5S)-4-cyclopropyl-5-ethyl-4-hydroxypyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), tris(dibenzylideneacetone)dipalladium(0) (79 mg) and cesium carbonate (786 mg), and in the same manner as in Example 62, the title compound was obtained as pale-yellow crystals (yield: 104 mg, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:29])[C:16](=[O:28])[C:17]([CH3:27])=[C:18](OS(C(F)(F)F)(=O)=O)[C:13]=2[C:12](=[O:30])[N:11]([CH3:31])[C:10]1=[O:32].[NH2:33][C:34]1[CH:35]=[C:36]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:37]=[CH:38][CH:39]=1.CN(C)C(=O)C.N1C(C)=CC=CC=1C>CO.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:29])[C:16](=[O:28])[C:17]([CH3:27])=[C:18]([NH:33][C:34]3[CH:35]=[C:36]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:37]=[CH:38][CH:39]=3)[C:13]=2[C:12](=[O:30])[N:11]([CH3:31])[C:10]1=[O:32]
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)c2c(=O)n(C)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Solvent: CO
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(Nc2cccc(NS(C)(=O)=O)c2)c2c(=O)n(C)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 130 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To trifluoromethanesulfonic acid 1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 70 (3.00 g) obtained in Step 6 and N-(3-aminophenyl)methanesulfonamide 44 (1.14 g) were added N,N-dimethylacetamide (6.00 ml) and 2,6-lutidine (0.712 ml), and the mixture was stirred at 130° C. for 4 hrs. After allowing to cool to room temperature, methanol/water [1:2 (volume ratio), 18.0 ml] was added under stirring. The crystals were collected by filtration and dried to give N-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 71 (3.13 g, yield 98%) as a pale-gray solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:27])[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2].C=O.[C:30]([BH3-])#N.[Na+]>CO>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([CH3:30])[CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:27])[CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: [BH3-]C#N
Reactant: N#Cc1c(NC(=O)C(c2ccccc2)c2ccccc2)sc2c1CCNC2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2c(sc(NC(=O)C(c3ccccc3)c3ccccc3)c2C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-2,2-diphenyl-acetamide (prepared in Example 8, step 1; 75 mg; 0.15 mmol) and formaldehyde (0.1 mL of 37% solution) in dry methanol at room temperature was added sodium cyanoborohydride (14.5 mg; 0.23 mmol). The mixture was allowed to stir for 1 hour at room temperature then concentrated in vacuo. The residue was taken up into methylene chloride and washed with water. The organic layer was dried (sodium sulfate) and concentrated in vacuo to give 50 mg (85%) of N-(3-Cyano-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-2,2-diphenyl-acetamide. ES-HRMS m/e calcd for C23H21N3OS (M+H+) 388.1478, found 388.1481.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([N:6]1[C:14]2[C:13]([F:15])=[CH:12][N:11]=[CH:10][C:9]=2[C:8]([I:16])=[CH:7]1)[CH3:5].[CH3:18]C(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]([N:6]1[C:14]2[C:13]([F:15])=[CH:12][N:11]=[CH:10][C:9]=2[C:8]([I:16])=[CH:7]1)([CH3:18])[CH3:5]
Reactant: COC(=O)C(C)n1cc(I)c2cncc(F)c21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)n1cc(I)c2cncc(F)c21
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a stirred solution of 2-(7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-1-yl)-propionic acid methyl ester (8 g, 22.98 mmol) in dry THF (80 mL) was added Mel (1.85 mL, 29.87 mmol) and the flask was placed in a water bath. Potassium tert-butoxide (1M in THF, 29.87 mL, 29.87 mmol) was added over 10 minutes and the mixture was stirred for an additional 10 minutes. Then reaction was quenched with water and few drops of 0.2M HCl and then diluted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulphate and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with 0-20% EtOAc in Hexane to afford the title compound as light yellow solid (78%, 6.5 g).
Reaction SMILES: [C:1]1([CH:7]([NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](O)(=[O:30])[CH2:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[C:1]1([CH:7]([NH:18][C:19]([CH2:20][NH:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1ccccc1
Product: O=C(CNC(=O)c1ccccc1)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]) and hippuric acid.
Reaction SMILES: C([O-])(=O)C.[K+].[F:6][C:7]1[CH:12]=[C:11](B(O)O)[CH:10]=[CH:9][N:8]=1.Br[C:17]1[CH:30]=[C:29]([F:31])[C:28]2[O:27][C:26]3[C:21](=[CH:22][C:23]([OH:32])=[CH:24][CH:25]=3)[C@:20]3([N:37]=[C:36]([NH:38]C(=O)OC(C)(C)C)[CH2:35][O:34][CH2:33]3)[C:19]=2[CH:18]=1.C(#N)C.O1CCOCC1>[Cl-].[Na+].O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[NH2:38][C:36]1[CH2:35][O:34][CH2:33][C@:20]2([C:19]3[CH:18]=[C:17]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([F:6])[CH:12]=4)[CH:30]=[C:29]([F:31])[C:28]=3[O:27][C:26]3[C:21]2=[CH:22][C:23]([OH:32])=[CH:24][CH:25]=3)[N:37]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(-c3ccnc(F)c3)cc12
Temperature: 100 °C
Yield: 38.4 %

Procedure:
A microwave vial was charged with potassium acetate (6.14 mg, 0.063 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.77 mg, 2.504 μmol), and 2-fluoropyridin-4-ylboronic acid (4.23 mg, 0.030 mmol). The (S)-tert-butyl 2′-bromo-4′-fluoro-7′-hydroxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-5-ylcarbamate (0.012 g, 0.025 mmol) was added as a solution in 1:1 acetonitrile/dioxane (1 mL). Water (0.1 mL) was added. Argon was blown through the vessel, which was then sealed and heated in a 100° C. oil bath for 6 h. The mixture was cooled, diluted with brine (10 mL), and the aqueous layer was extracted with 10% MeOH-DCM (3×20 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (20% MeOH in DCM) to afford 3.8 mg of (S)-5-amino-4′-fluoro-2′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@:8]2([CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH2:10]2)[CH2:7][N:6]1[C:22](=[O:36])[C@@H:23]([NH:28]C(OC(C)(C)C)=O)[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:28][C@@H:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]([N:6]1[C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:9][C@@:8]2([CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH2:10]2)[CH2:7]1)=[O:36]
Reactant: COC(=O)[C@@H]1C[C@@]2(CC(=O)N(c3cccc(Cl)c3)C2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@]2(CC(=O)N(c3cccc(Cl)c3)C2)CN1C(=O)[C@@H](N)C(C)(C)C

Procedure:
The compound (3S,5R)-methyl-2-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (C7a) (36.9 mg, 70.6 pimp was dissolved in CH2Cl2 (1.0 ml) and treated with trifluoroacetic acid (0.3 ml) for 6 hrs at room temperature. The reaction was concentrated to dryness to give (3S,5R)-methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (D7a) (70.6 μmol). The minor diastereomer (3S,5S)-methyl-2-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-7-(3-chloro phenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (C7b) (9.4 mg, 18 μmol) was treated similarly to give (3S,5S)-methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (D7b) (18 μmol, 100%).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH2:41][C@@H:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH:41]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reaction time: 0.08 h

Procedure:
A suspension of CuBr2 (20.88 g, 93.5 mmol) and HMTA (13.1 g, 93.5 mmol) in degassed DCM (250 ml) was treated with DBU (14.0 ml, 93.5 mmol) and the dark solution formed was stirred in a water bath for 5 minutes. A solution of ethyl(4S)-2-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-4,5-dihydro-1,3-oxazole-4-carboxylate (preparation 152) (9.24 g, 23.4 mmol) in degassed DCM (30 ml) was added dropwise to the reaction mixture and stirred at room temperature for a further 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with a 1:1 solution of NH3(aq): NH4Cl. The aqueous extract was washed with EtOAc (2×380 ml). The combined organic extracts were washed with 2M HCl (500 ml), sat. NaHCO3 (500 ml) and brine (500 ml). The organic extracts were dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (0:100) gradually changing to (25:75) to afford the title compound as colourless oil which formed needles on standing (7.39 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]1=[O:20].C([O-])=O.[NH4+]>[Pd].CO>[NH2:13][C:11]1[C:10]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]=2[CH:12]=1
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])CCCC(=O)N2C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1cc2c(cc1N)CCCC(=O)N2C
Temperature: 80 °C
Yield: 99.3 %

Procedure:
In a microwave tube, 316 mg of 1-methyl-7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are introduced into 20 ml of methanol. 443 mg of ammonium formate and 363 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to obtain 280 mg of 7-amino-1-methyl-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a colourless gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=3)[N:8]=2)=[CH:3][CH:2]=1.[ClH:24]>O>[ClH:24].[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Agent: Cl
Solvent: O
Product: Nc1ccc(Nc2nccc(-c3ccncc3)n2)cc1

Procedure:
A 2.85 g amount of N-[4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide was added to a mixture of 10 ml of concentrated hydrochloric acid and 10 ml of water. The reaction mixture was heated at reflux for 90 minutes, then evaporated in vacuo to obtain a solid. The solid was recrystallized from 3A ethanol/water and gave 2.31 g of the desired product as a yellow crystalline solid, mp 292°-295° C.
Reaction SMILES: CC([S@@](/[N:7]=[C:8]1\[CH2:9][CH2:10][C@@H:11]2[C@H:15]\1[CH2:14][N:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:12]2)=O)(C)C.C(N1C[C@H]2/C(=N/[S@](C(C)(C)C)=O)/CC[C@H]2C1)C1C=CC=CC=1>>[F:25][C:23]([F:24])([F:26])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH2:14][C@H:15]2[C@H:8]([NH2:7])[CH2:9][CH2:10][C@H:11]2[CH2:12]1
Reactant: CC(C)(C)[S@](=O)/N=C1\CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]12
Agent: CC(C)(C)[S@](=O)/N=C1\CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
(3aS,4R,6aR)-2-(3-(Trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine was prepared according to the procedure described in Example 16 Steps A-E substituting (S,E)-2-methyl-N-((3aS,6aR)-2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)propane-2-sulfinamide from Step A in Example 152 for (S,E)-N-((3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide in Step A-E of Example 16 to give (3 aS,4R,6aR)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.78 (s, 1H), 7.59 (d, J=6.0, 2H), 7.45 (t, J=7.7, 1H), 4.94 (br s, 2H), 3.53 (s, 2H), 3.13 (dd, J=5.1, 11.6, 1H), 2.63-2.54 (m, 1H), 2.49 (dd, J=3.3, 9.0, 1H), 2.35 (dd, J=7.5, 9.0, 1H), 2.32 (d, J=5.9, 2H), 2.21-2.13 (m, 1H), 1.96 (dt, J=6.0, 8.7, 1H), 1.88 (td, J=3.9, 9.7, 1H), 1.38-1.29 (m, 2H); MS (ESI+) m/z 284 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])(C)(C)C.CN([CH:20]=[O:21])C.O.O.C(O)(=O)C(O)=O>CCOCC.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[O:4][CH:5]=[CH:6][C:2]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Brc1ccoc1C1OCCO1
Agent: O=C(O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccoc1C1OCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
2-(3-Bromo-2-furyl)-1,3-dioxolane (438 mg, 2.0 mmol) is dissolved in Et2O (5 mL) in an oven-dried flask, under nitrogen, cooled to −78° C., treated dropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 h. DMF (178 μL, 2.3 mmol) in Et2O (2 mL) is added dropwise, the mixture stirred for 4 h at −78° C., then treated with oxalic acid dihydrate (504 mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed and the mixture allowed to warm to rt over 1 h. The mixture is diluted with water (20 mL) and EtOAc (20 mL), the layers are separated and the aqueous layer extracted with EtOAc (1×20 mL). The organics are dried over Na2SO4 and concentrated to a yellow oil. The crude material is chromatographed over 12 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 228 mg (68%) of 2-(1,3-dioxolan-2-yl)-3-furaldehyde as a pale yellow oil. MS (EI) m/z: 168 (M+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8](S(F)(=O)=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(NCC)C>ClCCCl>[C:4]([OH:6])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(O)c1cc(S(=O)(=O)F)ccc1Cl
Solvent: CCNCC
Solvent: ClCCCl
Product: O=C(O)c1ccccc1

Procedure:
A mixture of 2-chloro-5-(fluorosulfonyl)benzoic acid (11.93 g, 0.05 mol), diethylamine (10.97 g, 0.15 mol) and 1,2-dichloroethane (100 ml) is refluxed for 8 hours. The reaction mixture is evaporated, and the residue is dissolved in ethyl acetate. A solid is collected by filtration, and the filtrate is evaporated to dryness to afford 15.5 g of 2-chloro-5-diethylaminosulfonyl)benzoic acid.