Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[C:22](=[O:24])=[O:23].[K+].[Br-]>C1COCC1>[C:22]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1)([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Brc1ccc2c(c1)COCC2
Agent: [Br-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)COCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 7-bromoisochroman (7 g; 32.86 mmol) in THF (100 ml) was cooled to -78° C. and treated with 40.6 ml of a 1.7M solution of tert-butyllithium in pentane (69 mmol; 2.1 eq). Powdered dry ice (excess) was added to the red anion solution within 45 seconds. The reaction mixture was stirred for 30 minutes at -78° C. and 1 hour at room temperature. The reaction was quenched with 60 ml of 1N HCl and extracted with 3×70 ml of ether. The ether layers were combined and washed with brine until the pH was neutral, dried with MgSO4, and concentrated in vacuo. The product was obtained as a white solid, mp 140°-142° C. (5.7 g; 82%). 1H NMR (CDCl3): δ2.95 (t, 2H); 4.03 (t, 2H); 4.83 (s, 2H); 7.24 (t, 1H); 7.89 (s, 1H); 7.92 (d, 1H). IR (KBr): 2954, 2561, 1684, 1427, 1293, 1108 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=O.O.[NH2:13][NH2:14].C(O)(=O)C>>[N:1]1[C:2]2[C:10](=[O:11])[NH:13][NH:14][C:7](=[O:9])[C:3]=2[N:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2nccnc21
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2nccnc12
Temperature: 25 °C

Procedure:
The title compound was prepared according to a literature procedure (Paul, D. B. Aust. J. Chem. 1974, 27, 1331). As described therein, 2,3-pyrazinedicarboxylic anhydride (5.00 g, 33.3 mmol), hydrazine hydrate (2.8 g, 56 mmol), and acetic acid (40.4 ml, 33.3 mmol) were mixed at RT. White precipitated crashed out. The reaction was heated under reflux for approximately 20 min. The reaction was cooled to RT and the solids were filtered, washed with water, and dried under vacuum. The product, 6,7-dihydropyrazino[2,3-d]pyridazine-5,8-dione was obtained as white solid. 1H NMR (Bruker, 400 MHz, D2O) ppm: 8.87 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([CH:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[C@@H]1COC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OCC4C(C)(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 0.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-4-tert-butyloxazolidin-2-one (286 mg), the title compound (9 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:25])([F:26])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([N:32]3[CH2:33][C:30]([F:34])([F:29])[CH2:31]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Reactant: FC1(F)CNC1
Agent: Cl
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N2CC(F)(F)C2)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and 3,3-Difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials and isolated (35 mg, 58%); MS (ESI, m/z): 464.6 (M+H+).
Reaction SMILES: [P:1]([OH:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)(O)[O-].[Na+].S([O-])(O)(=O)=O.S(Cl)(O[CH2:28][Cl:29])(=O)=O>O.ClCCl>[P:1]([O:13][CH2:28][Cl:29])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: CC(C)(C)OP(=O)(O)OC(C)(C)C
Reactant: O=S(=O)(Cl)OCCl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Yield: 52.3 %

Procedure:
To a well stirred suspension of di-tert-butyl hydrogen phosphate (4.7 g, 22.47 mmol) in water (186 ml) was added sodium bicarbonate (7.5 g, 89.52 mmol) followed by tetra-n-butylammomium hydrogen sulphate (760 mg, 2.238 mmol). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added dichloromethane (112 ml) at 0° C. and it was stirred for 10 min followed by the addition of chloromethyl chlorosulphate (4.4 g, 26.85 mmol) in dichloromethane (75 ml) at same temperature. The resultant mixture was vigorously stirred overnight at room temperature. The organic layer was separated, washed with brine and evaporated under reduced pressure to yield 3.04 g of product as pale yellow oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH:24]1[C:51](=[O:52])[N:26]2[CH:27]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[C:28]3([S:40][C@H:25]12)[CH2:33][CH2:32][N:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:30][CH2:29]3.C(N(CC)CC)C.[C:60]1([CH2:66][C:67](Cl)=[O:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>ClCCl>[C:34]1([N:31]2[CH2:32][CH2:33][C:28]3([CH:27]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])[N:26]4[C:51](=[O:52])[CH:24]([NH:23][C:67](=[O:68])[CH2:66][C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[C@H:25]4[S:40]3)[CH2:29][CH2:30]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(c4ccccc4)CC3)S[C@H]12
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(c4ccccc4)CC3)S[C@H]12
Temperature: 15 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a suspension of 1.53 g (0.002 mole) of benzyl 6-amino-1'-phenyl-spiro[penam-2,4'-piperidine]-3-carboxylate di-p-toluenesulfonate (prepared according to the method described in Example 1.8.3. of our Application Ser. No. 06/162,616, filed June 24, 1980) in 100 ml of anhydrous dichloromethane is added all at once 404 mg (0.004 mole) of triethylamine in 10 ml of dichloromethane. The solution is cooled to a temperature of from 0° to -5° C. and then there are simultaneously added dropwise a solution of 340 mg (0.022 mole) of phenylacetyl chloride in 30 ml of dichloroemethane and a solution of 220 mg (0.022 mole) of triethylamine in 30 ml of dichloromethane, the addition taking place over the course of about 1 hour. Thereafter, the reaction mixture is stirred for 3 hours at 15° C., then successively washed with water, with a saturated aqueous solution of sodium hydrogen carbonate and again with water. After evaporating the solution to dryness and recrystallizing the residue from ethyl acetate/hexane (1:3 v/v), there are obtained 950 mg of benzyl 1'-phenyl-6-(2-phenylacetamido)-spiro[penam-2,4'-piperidine]-3-carboxylate. Yield: 88%; M.P. 120°-121° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.[N+](=[CH2:27])=[N-]>CO.CCOCC>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:27])=[O:23])[CH2:3]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 0.17 h

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (350 mg.) in methanol (20 ml.) and ether (10 ml.) was treated with a dry ethereal solution of diazomethane. After 10 minutes, any unreacted diazomethane was destroyed by the addition of a drop of glacial acetic acid and the mixture was evaporated to small bulk. This was taken up in ether and washed with dilute sodium hydrogen carbonate solution, with water, dried and evaporated to a foam. The product was crystallised from acetone and petrol to give title compound (28/ mg.) as off white needles; m.p. 162 163°; [α]D + 77°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])=[CH:17][CH:18]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.5 mL, 5.9 mmol) was added to a suspension of (4-bromophenoxy)acetic acid (0.462 g, 2.0 mmol) in methylene chloride (10 mL) and 2 drops of N,N-dimethylformamide. The mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure. The residue was diluted with methylene chloride (10 mL), cooled with ice-water bath, and 1M of sodium hydroxide aqueous solution (3.0 mL) was added. To the mixture was added pyrrolidine (167 μL, 2.0 mmol). The mixture was stirred and allowed to warm to RT. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was directly used in next step without further purification (550 mg, 96.7%). LCMS: (M+H)=286.0/284.0
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]1[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]1[NH2:22]>N1C=CC=CC=1>[CH3:14][CH:15]1[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]1[NH:22][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: CC1CCCC(N)C1C
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Product: CC1CCCC(NC(=O)c2cnc3ccccc3n2)C1C
Yield: 58.8 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2,3-dimethylcyclohexylamine (115 mg, 0.90 mmol), and pyridine (5 mL) yielding 150 mg (59%) of (163):
Reaction SMILES: ClC1C=C([C@H](CCN2CCC(N(C(=O)C(F)(F)F)CCNC(=O)C(F)(F)F)CC2)[CH2:10][N:11](C)[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=1Cl.FC(F)(F)C(N(CCCNC(=O)C(F)(F)F)C1CCNCC1)=O.ClC1C=C(C(CC=O)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl>>[CH3:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C[C@@H](CCN1CCC(N(CCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C(NCCCN(C(=O)C(F)(F)F)C1CCNCC1)C(F)(F)F
Product: CNC(=O)c1ccccc1

Procedure:
(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-trifluoroacetyl)-[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidino]butyl]-N-methylbenzamide. Using the procedure of Example 1, replacing 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine by 4-[(2,2,2-trifluoroacetyl)-[3-(2,2,2-trifluoroacetylamino)propyl]amino]piperidine, and N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide by the (S)-enantiomer, the N-methylbenzamide was obtained; MS: m/z=683(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Cl[C:25]1[S:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[S:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][N:29]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ncc(S(N)(=O)=O)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (336 mg, 1.0 mmol) and 2-chloro-thiazole-5-sulfonamide (199 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (209 mg, 42%). MS (ISN) 496.0 [(M−H)−]; mp 123° C.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C(F)(F)F)cc2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(4-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a solution of 4-fluoro-2-methylbenzoic acid (4.0 g, 26.0 mmol) in THF (30 mL) in a pressure vessel was added cesium carbonate (8.45 mg, 26.0 mmol) and iodomethane (2.0 M in tert-butyl methyl ether, 13.0 mL, 26.0 mmol). The vessel was sealed and the reaction was stirred at 70° C. for 16 h. After cooling to rt, the reaction was quenched with saturated sodium bicarbonate (10 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL), and then the organic phase was dried (Na2SO4) and concentrated under reduced pressure to give the crude product. This material was triturated with acetone and hexanes to afford pure product (3.8 g, 87%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ 2.60 (s, 3H), 3.86 (s, 3H), 7.05-7.12 (m, 2H), 7.96 (s, 1H); ES-MS m/z 168.2 (MH+); HPLC RT (min) 3.20.
Reaction SMILES: [CH3:1]COCC.[CH3:6][N:7]([CH3:21])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][N:7]([CH3:21])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=[CH2:1])[CH2:10][CH2:9]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CCOCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Tert-BuOK (0.550 g, 4.74 mmol) was provided in abs. ether (10 mL) in argon and methyl triphenyl phosphonium bromide (1.89 g, 4.74 mmol) added. The mixture was then heated to 40° C. for 30 min. After this reaction time 4-dimethylamino-4-phenylcyclohexanone (1.00 g, 4.60 mmol) dissolved in abs. THF (10 mL) was carefully added in drops and the reaction solution was heated to 50° C. for 5 h. The reaction batch was stirred overnight at room temperature and concentrated in a vacuum until dry. The residue was taken up in dioxan (50 mL) and mixed with HCl/dioxan (5 mL). The precipitated solid was aspirated and washed with ether. The isolated hydrochloride was basified with 2 N NaOH and extracted with dichloromethane (2×80 mL). The organic phase was dried over Na2SO4, filtered and concentrated to low volume in a vacuum.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6])[CH2:3][OH:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:8]([O:7][C@H:5]([CH3:6])[C@H:2]([NH:1][C:17]1[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([Cl:12])[N:18]=1)[CH2:3][OH:4])([CH3:10])([CH3:9])[CH3:11]
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)CO
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A solution of (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (267 mg, 1.35 mmol, 1.1 equiv), 2,4-dichloro-6-methylpyrimidine (200 mg, 1.23 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.54 mL, 3.1 mmol, 2.5 equiv) in 1,4-dioxane (6 mL) was heated at 75° C. for 4 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, white solid) in 24% yield. 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 4.02 (m, 2H), 3.79-3.64 (m, 2H), 2.30 (s, 3H), 1.22 (s, 9H), 1.18 (d, J=6.2 Hz, 3H); MS m/z 288.1 (M+H)+; Rt-0.59 min.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: OCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCO
Temperature: -20 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 85.0 g (0.904 mole) of 1,5-pentanediol and 30.3 g (0.30 mole) of triethylamine in 350 mL of dry CH2Cl2 at -20° C. was added dropwise a solution of 28.5 g (0.25 mole) of methanesulfonylchloride in 100 mL of CH2Cl2 over 2 hours under nitrogen atmosphere. The solution was stirred at 2 hours at -20° C. and then at -4° C. for 18 hours. The reaction mixture was washed with H2O, 1N HCl, H2O, then dried and evaporated. The residual oil was chromatographed on a silica gel column, eluting with EtOAc-CH2Cl2 (2:8). After combining the appropriate fractions there was obtained 25.7 g (56.5%) of 5-hydroxypentylmethylsulfonate as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@H:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C@H:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@@H](N)CO
Product: CC(C)C[C@H](CO)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2R)-2-amino-4-methyl-1-pentanol (CAN 53448-09-2) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2165 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[NH:17][C:16](=S)[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1.[NH3:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[N:17]=[C:16]([NH2:23])[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1
Reactant: N
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(=S)N1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(N)=N1
Temperature: 60 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
A mixture of (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-thione (300 mg, 742 μmol, Eq: 1.00) and ammonia (7 N in MeOH) (7.87 g, 10 ml, 70.0 mmol, Eq: 94.3) was stirred in a sealed tube for 48 hours at 60° C. Extracted with ethyl acetate and sat. NaHCO3-sol., dried the organic layer over Na2SO4, filtered and evaporated. The residue was chromatographed with ethyl acetate to give (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]deca-2,9-dien-10-ylamine (249 mg, 643 μmol, 86.7% yield) as a white foam. MS (ISP): m/z=387.3 [M+H]+ and 389.3 [M+2+H]+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH2:14])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=1)#[N:33]>>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH:14][C:40]([C:37]2[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][N:38]=2)=[O:41])=[CH:8][CH:7]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H](N)Cc2ccc(OC(C)(C)C)cc2)CC1
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)c2ccc(C#N)cn2)CC1
Yield: 47.8 %

Procedure:
Reaction of 2.5 g of t-butyl [[1-[3-(p-t-butoxyphenyl)-L-alanyl]-4-piperidinyl]oxy]acetate with 0.85 g of 5-cyano-2-picolinic acid (as in Example 1d) yields 1.55 g of t-butyl [[1-[3-(p-t-butoxyphenyl)-N-[[5-cyano-2-pyridyl]carbonyl]-L-alanyl]-4-piperidinyl]oxy]acetate. M.p. 122-123° C. (diethyl ether/petroleum ether 4:1). MS (FAB): 565 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:11]1[O:13][CH2:12]1.[H-].[Na+].O>O1CCOCC1>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8]1
Reactant: C1CO1
Reactant: Oc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCCOc1cccc2cc[nH]c12
Temperature: 100 °C
Reaction time: 120 h
Yield: 33.9 %

Procedure:
A mixture of 7-hydroxyindole (1.00 g, 7.51 mmol) and ethylene oxide (0.33 g, 7.50 mmol) in dioxane (3 mL) was placed in a reaction tube. NaH (60% in oil; 0.100 g, 2.45 mmol) was added and the reaction mixture was stirred at 100° C. for 5 days. The reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 0.45 g (34%) of the title product. Pos-EI-MS shows M+ and 5 ions supporting the stated structure. HRMS m/z calcd for C10H11NO2 (M)+177.0790, found 177.0799.
Reaction SMILES: FC1C=[C:4](C=C(F)C=1)[CH2:5][N:6]1C=CN=C1S.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[SH:28])=[CH:19][CH:18]=1>>[NH2:6][CH2:5][CH2:4][S:28][C:24]1[N:23]([C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Fc1cc(F)cc(Cn2ccnc2S)c1
Reactant: Sc1nccn1-c1ccc(Cl)cc1
Product: NCCSc1nccn1-c1ccc(Cl)cc1

Procedure:
The procedure of Example 1 wherein 1-(3,5-difluorobenzyl)-2-mercaptoimidazole is replaced by 1-(4-chlorophenyl)-2-mercaptoimidazole yields 2-(2-aminoethylthio)-1-(4-chlorophenyl)imidazole.