Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH2:19](Br)[C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][C:20]#[CH:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(NC(=O)C(C)(C)C)c1C(=O)OC

Procedure:
A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 14, 4.57 g), propargyl bromide (80% solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20% to give methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as an oil which crystallised on standing to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][F:17].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][F:17])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FCCNc1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CCF)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-fluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification to give a first batch of compound (light yellow solid). A second chromatographic purification of the remaining impure fractions and mother liquor gave a second batch of compound. Yellow solid (25% overall). MS (ESI): m/z=491.08 [M+H]+.
Reaction SMILES: C(OC([O:11][C:12]1([CH2:51][CH3:52])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:51]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)[CH3:52]
Reactant: [H][H]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccco1
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccco1

Procedure:
A mixture of Compound 56 (180 mg, 0.25 mmol), 10% palladium on carbon (36 mg, 20%) in 6 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>O>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Water (30 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxybenzothioamide (3.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (2.52 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained for about 20 minutes. The mass was then filtered. The wet solid was dried at about 60° C. to a constant weight to yield 4.0 g of the title compound. Purity by HPLC: 95.74%.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=O)[C:6]([Cl:8])=[O:7].[CH3:11][O:12][C:13](=[O:23])[C:14]([CH3:22])([C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1)[CH3:15]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:23])[C:14]([C:16]1[CH:17]=[CH:18][C:5]([C:6]([Cl:8])=[O:7])=[CH:20][CH:21]=1)([CH3:22])[CH3:15]
Reactant: COC(=O)C(C)(C)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (500.0 mg, 3.75 mmol) in CH2Cl2 at −10° C. was added dropwise oxalyl chloride (476.0 mg, 3.75 mmol) in CH2Cl2. The mixture was stirred at this temperature for 30 min. Then a solution of 2-methyl-2-phenyl-propionic acid methyl ester (178.0 mg, 1.0 mmol) in CH2Cl2 was added. The resulted mixture was stirred at −10° C. for 1 hr and rt overnight. The mixture was filtered through a pad of celite, the solvent and excess oxalyl chloride was removed under reduced pressure. The residue was dissolved in chlorobenzene and refluxed for 4 hr. Solvent was removed and the residue was dried to give 2-(4-chlorocarbonyl-phenyl)-2-methyl-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N+:3]=1[O-:18]
Reactant: COc1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
2-chloro-5-methoxy-pyridine (200 mg, 1.39 mmol) and mCPBA (360 mg, 2.09 mmol) was dissolved in CH2Cl2 (10 ml). The mixture was stirred at room temperature for 2 days. The mixture was then diluted with CH2Cl2 and washed with 10% aqueous K2CO3 and brine and dried over Na2SO4. The solvent were removed in vacuo affording 140 mg (63%) of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.O.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:12]/[NH2:13]
Reactant: NN
Reactant: O=Cc1c(Br)cncc1Br
Solvent: O
Product: N/N=C/c1c(Br)cncc1Br
Temperature: 120 °C
Yield: 49.1 %

Procedure:
In analogy to GP 1, 54 mg of 3,5-dibromo-pyridine-4-carbaldehyde (0.2 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 1 mL 1-propyl alkohol, treated with 30 μL 80% hydrazine hydrate (0.61 mmol, 3 eq.) and heated to 120° C. for 30 min (employing a Biotage Initiator® microwave oven). The precipitate was filtered and washed with cold 1-propyl alkohol to yield 27 mg of the hydrazone (0.1 mmol, 50% yield).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](#[N:11])[CH:9]=[CH2:10].C[O-].[Na+]>>[C:1]1([S:7][CH2:10][CH2:9][C:8]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC#N
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: N#CCCSc1ccccc1

Procedure:
β-Phenylmercaptopropionitrile was prepared according to the procedure of Example 1 using thiophenol (25.0 g; 0.23 moles), acrylonitrile (12.2 g; 0.23 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].C(O)[C@@H]([C@H]([C@@H](CO)O)O)O.C([O-])(=O)C>OCC(CO)O>[O:1]=[C:2]([OH:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)CO
Agent: CC(=O)[O-]
Agent: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: OCC(O)CO
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
In addition to xylonate, xylitol, glycerol and acetate were also produced. Glycerol and acetate were subsequently consumed, but the xylitol was not.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[N:12](COCC[Si](C)(C)C)[CH:11]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: COc1ccccc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Sc5ccccc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 47 %

Procedure:
(S)-2-(1-((5-((2-Methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (57 mg, 0.09 mmol) was treated with boron tribromide (1M in dichloromethane, 872 μL, 0.87 mmol) in dichloromethane (1.14 mL) and then with a solution of ammonia (7N in methanol, 1.14 ml, 7.98 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 100% dichloromethane ethyl acetate) to obtain 23 mg (47% yield, 90% purity) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH2:58])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:54])([F:53])[F:52].C(N(CC)CC)C>CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH:58][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:53])([F:54])[F:52]
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then (R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propylamine hydrochloride (81 mg, 0.3 mmol) and triethylamine (82 mg, 0.81 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 98 mg (73%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propyl]-amide as white solid. LC/MS (method 3): Rt=2.03 min; m/z=498.22 (M+H+). 1H-NMR: δ (ppm)=8.20 (1H, d), 7.83 (1H, d), 7.67 (1H, s), 7.50 (1H, d), 7.25 (1H, s), 4.96 (1H, d), 4.83-4.91 (m, 2H), 4.18-4.30 (2H, m), 3.92-4.01 (2H, m), 3.79-3.85 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.76-1.85 (3H, m), 1.54-1.60 (1H, m), 1.19 (3H, d), 0.90 (3H, t).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: NC1CCc2cc(Cl)ccc21
Reactant: Clc1nc2ccccc2[nH]1
Product: Clc1ccc2c(c1)CCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1-amino-5-chloroindane (prepared by Procedure B from 5-chloro-1-indanone) by Procedure A (30 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 242-243° C.). MS(ES+) m/z 284 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.92 (m, 1H), 2.55 (m, 1H), 2.83 (m, 1H), 2.95 (m, 1H), 5.32 (m, 1H), 6.81-6.97 (m, 3H), 7.10-7.21 (m, 3H), 10 7.26-7.33 (m, 2H), 10.8 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1([C:15]([O:17]CC)=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O.O>[CH2:1]([NH:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CNC(=O)NCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To the solution of ethyl 1-((3-benzylureido)methyl)cyclopropanecarboxylate (Compound V-3)(1.6 g, 5.8 mmol) in tetrahydrofuran/methanol/water (2:3:1, 20 ml), lithium hydroxide monohydrate (487 mg, 11.6 mmol) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water (25 ml) and washed with ether (25 ml). The aqueous layer was acidified with 10%-citric acid (15 ml) and extracted with chloroform (30 ml). The organic layer was washed with brine (25 ml) and dried over magnesium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the title compound (1.08 g, 77%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30].C(N)CN.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:29]#[N:30])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(CCCc2cc(Br)ccc2OCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: NCCN
Product: COC(=O)c1ccc(CCCc2cc(C#N)ccc2OCc2ccccc2)cc1
Yield: 66.1 %

Procedure:
A mixture of methyl 4-[3-(2-benzyloxy-5-bromophenyl)propyl]-benzoate (0.5 g) and CuCN (250 mg) in DMF (20 ml) was heated at reflux for 18 hours, poured into ethylene diamine (20 ml) and water (60 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried (magnesium sulphate), filtered and evaporated to give methyl 4-[3-(2-benzyloxy-5-cyanophenyl)propyl]-benzoate (290 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d,15 Hz,1H), 2.59 (d,15 Hz,1H), 2.6-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s,1H), 6.72 (d,7 Hz,1H), 6.98 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.82 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29].O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Reactant: CCCCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCNc1nc(Nc2ccc(NC(=O)OCCCC)cc2)ncc1Br

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (0.31 mmol, prepared in analogy to procedure 21) was dissolved in THF (20 ml), triethyl amine (0.33 mmole) and butyl chloroformate (0.33 mmole) were added at room temperature and the reaction was stirred at this temperature until the starting material disappeared (TLC, 3 h). The reaction was poured into water and [4-(5-Bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-carbamic acid butyl ester was isolated by filtration. Yield: 91 mg (70%). ESI-MS: 419.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:14]C1C=C(C=CC=1)N>>[CH3:13][N:8]([C:5]1[CH:4]=[C:3]([CH3:14])[CH:2]=[CH:7][CH:6]=1)[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CN(c1ccc(I)cc1)S(C)(=O)=O
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(N(C)S(C)(=O)=O)c1

Procedure:
N-Methyl-N-(3-tolyl)methanesulphonamide was prepared as for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide described in Example 3, except that 3-methylaniline was used in place of 4-iodoaniline.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[N:17][N:16]=2)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28](C)[NH:27][C:26]=1[C:32](NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=O>>[Cl:30][C:29]1[C:25]([Cl:24])=[C:26]([CH3:32])[NH:27][C:28]=1[C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[N:17][N:16]=2)[CH2:13][CH2:14]1)=[O:7]
Reactant: COC(=O)c1nnc(N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Product: COC(=O)c1nnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)o1

Procedure:
The title compound was synthesized by an analogous method to Example 42 by coupling methyl 5-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1,3,4-oxadiazole-2-carboxylate (Intermediate 160) with 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3). De-BOC and coupling should be separate steps.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:12][CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 1,2,3,4-tetrahydro-2-naphthoic acid (2.50 g, 14.2 mmol) in 100 ml THF was treated with LiAlH4 (681 mg, 17.04 mmol) and the reaction mixture was heated at reflux for 5 hours. The suspension was cooled to 0° C. and quenched by addition of solid Na2SO4 ·10H2O. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration. Concentration of filtrate in vacuo gave a yellowish oil (2.28 g, 98.8%); 1H NMR (CDCl3, 300 MHz) δ 1.43 (m, 1H), 2.00 (m, 2H) 2.51 (dd, J1 =16.5 Hz, J2 =10.8 Hz, 1H), 2.85 (m, 3H), 3.65 (dd, J1 =6.3 Hz, J2 =1.2 Hz, 2H), 7.09 (s, 4H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH2:7]([N:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])[CH3:8]>>[CH2:7]([N:9]([CH2:13][CH3:14])[C:10]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:11])[CH3:8]
Reactant: CCN(CC)C(=O)Cl
Reactant: OC1CCNC1
Product: CCN(CC)C(=O)N1CCC(O)C1

Procedure:
A method of preparing each of the foregoing compounds is presented in the following examples. In general, however, in the 1-methyl pyrrolidine series (compounds I and II) cyclization of 1,4-dibromo-2-butanol to yield 1-methyl-3-pyrrolidinol was followed by chlorination to give 3-chloro-1-methyl pyrrolidine. Substitution with benzylamine provided the nitrogen substituent 3-(N-benzyl)amino-1-methyl pyrrolidine which was acylated with diethylcarbamyl chloride and debenzylated to yield compound I. Methylation of 3-(N-benzyl)amino-1-methyl pyrrolidine gave compound 3-(N-benzyl-N-methyl)-amino-1-methyl pyrrolidine which was debenzylated to 1-methyl-3-(N-methyl)amino pyrrolidine and acylated with ethyl chloroformate to give compound II. Synthesis of the 1-acylated pyrrolidine compounds III and IV commenced by treated commercially available 3-pyrrolidinol with diethylcarbamyl chloride to yield 1-diethylcarbamyl-3-hydroxy pyrrolidine. The 3-benzylamino analog 3-(N-benzyl)amino-1-diethylcarbamyl pyrrolidine was obtained by treatment of 1-diethylcarbamyl-3-hydroxy pyrrolidine with thionyl chloride followed by benzylamine. Subsequent methylation yielded the compound 3-(N-benzyl-N-methyl)amino-1-diethylcarbamyl pyrrolidine which, on debenzylation gave the compound III. Subsequent methylation of III yielded the compound IV.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.[N:28]1([S:32]([NH:35][C:36](=[O:55])[C:37]2[CH:42]=[C:41](Cl)[C:40]([O:44][CH2:45][CH:46]3[CH2:53][CH2:52][C:49]4([CH2:51][CH2:50]4)[CH2:48][CH2:47]3)=[CH:39][C:38]=2[F:54])(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([S:32]([NH:35][C:36](=[O:55])[C:37]2[CH:42]=[C:41]([CH:10]3[CH2:1][CH2:2]3)[C:40]([O:44][CH2:45][CH:46]3[CH2:53][CH2:52][C:49]4([CH2:51][CH2:50]4)[CH2:48][CH2:47]3)=[CH:39][C:38]=2[F:54])(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro- N-(methylsulfonyl)benzamide with N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide, the title compound was obtained as a colorless solid (0.39 g, 66%): 1H NMR (300 MHz, CDCl3) δ 8.74-8.59 (m, 1H), 7.64-7.54 (m, 1H), 6.64-6.52 (m, 1H), 4.31-4.18 (m, 4H), 3.93-3.81 (m, 2H), 2.35-2.20 (m, 2H), 2.13-2.00 (m, 1H), 1.99-1.72 (m, 5H), 1.40-1.20 (m, 2H), 1.02-0.85 (m, 4H), 0.73-0.61 (m, 2H), 0.37-0.14 (m, 4H); MS (ES+1) m/z 437.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:38])=[C:22](/[CH:26]=[C:27](/[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[F:37])\[C:28]#[N:29])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=2[F:38])[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[F:37])([C:28]#[N:29])[CH:9]([CH2:10][C:11]([CH2:12][CH3:13])([CH2:16][CH3:17])[CH2:14][CH3:15])[NH:8]1)=[O:18])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC(CC)(CC)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CC(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CCC(CC)(CC)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 56.8 %

Procedure:
In a manner similar to the method described in Example 100b, [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 106a (1.8 g, 7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.74 g, 5.6 mmol) prepared in Example 52a, AgF (1.1 g, 8.6 mmol), and triethylamine (1.95 mL, 14 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (1.8 g, 57%).