Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C.C(=O)(O)[O-].[Na+]>O>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCC1C(=O)N(CC)CCc2cc(N)c(OC)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCC1C(=O)N(CC)CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc21
Temperature: 120 °C

Procedure:
7-Amino-1,3-diethyl-8-methoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one (85 mg, 0.32 mmol;), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (120 mg, 0.36 mmol), and 10-camphorsulfonic acid (82.5 mg, 0.355 mmol) were charged to isopropyl alcohol (3 ml, 40 mmol) in a microwave reaction tube. The reaction was heated in microwave at 120° C. for 40 minutes. The resulting solution was poured into a mixture of 20 ml saturated sodium bicarbonate solution and 40 ml water and the aqueous solution was extracted with methylene chloride (4×10 ml portions). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a clear yellow oil. The oil was evaporated onto celite and the celite placed on silica gel (12 g Isco column) and eluted with 0-70% EtOAc in Hexanes to obtain N-{(1R,2R)-2-[5-Chloro-2-(1,3-diethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a beige powder. MP: 126-127° C.; 1H-NMR (CDCl3) δ 8.01 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H), 5.35 (d, J=7.8 Hz, 1H), 5.29 (d, J=7.8 Hz, 1H), 4.00-3.82 (m, 5H), 3.57 (p, J=7 Hz, 1H), 3.45 (m, 2H), 3.28-3.07 (m, 3H), 2.80 (d, J=2.8 Hz, 3H), 2.30-2.10 (m, 3H), 1.98-1.80 (m, 3H), 1.47-1.30 (m, 4H), 1.10 (t, J=7 Hz, 3H), 1.03 (t, J=7 Hz, 3H); LC/MS (ESI+): 565 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:12][C:13]([C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]3)=[N:19][N:18]2[CH:41]=1)=O)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13]([C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29](=[O:40])[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]([F:37])([F:39])[F:38])[CH2:27][CH2:28]4)=[N:19][N:18]3[CH:41]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 30 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to 4-fluorobenzylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 30% yield (0.035 g). m.p. 205-207° C. 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.77-7.5 (m, 5H), 7.38-7.27 (m, 3H), 7.03-6.94 (m, 2H), 6.9 (d, J=9.6 Hz, 1H), 4.58 (d, J=6 Hz, 2H), 4.06-3.94 (m, 1H), 3.93-3.81 (m, 1H), 3.69-3.54 (m, 2H), 3.52-3.42 (m, 2H), 3.36-3.27 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 163.7, 162.3, 160.5, 154.8, 137.8, 135.7, 134.2, 132.4, 129.6, 129.5, 126.9, 126.8, 126.7, 125.3, 124.4, 121.8, 118.4, 115.6, 115.3, 112.0, 46.2, 46.2, 45.6, 42.4, 41.2. MS (ES+) m/z 527.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.[CH:23]([C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][C:35]=1[OH:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:23]([C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][C:35]=1[O:36][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24]
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Reactant: BrCCCc1ccc(OCCCCOc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C=O)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
1.37 g (3.76 mmol) of 1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzene, 0.79 g (3.76 mmol) of ethyl 3-formyl-4-hydroxybenzoate [CAS No. 82304-99-2] and 0.78 g (5.64 mmol) of potassium carbonate are dissolved in 20 ml of DMF, and the mixture is stirred at 40° C. for 16 hours. It is then concentrated, and the residue is taken up in 200 ml of water and extracted with dichloromethane (three times 100 ml). The combined organic phases are dried (sodium sulphate) and concentrated, and the crude product is purified by chromatography on silica gel (mobile phase gradient cyclohexane-->cyclohexane/ethyl acetate 5:1). 1.45 g of product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[O:13][CH2:12][CH:11]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[O:13][CH2:12][CH:11]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: CCC(=O)NC1COc2cc([N+](=O)[O-])cnc2C1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCC(=O)NC1COc2cc(N)cnc2C1
Yield: 100.2 %

Procedure:
N-(3,4-Dihydro-7-nitro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (445 mg, 1.76 mmol) was dissolved in ethanol (80 ml) and SnCl2.2H2O (2 g, 8.82 mmol) was added. The resulting mixture was refluxed for 8 h and then the solvent was removed under vacuum. The raw material was dissolved in ethyl acetate and washed successively with 2 N aqueous NaOH (2×) and water. The organic layer was dried (Na2SO4), filtered through a pad of celite and evaporated to afford the crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (390 mg, 99%) as a pale yellow powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[C:31]([CH2:33][O:34]C3CCCCO3)[CH:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:42])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cc(COC4CCCCO4)cn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cc(CO)cn3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M58) (642 mg, 1.05 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (365 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[NH2:12].C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:12][C:18](=[O:17])[NH:19][C:6]2=[O:8]
Reactant: N#C[O-]
Reactant: COc1cccc(C(=O)O)c1N
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c(=O)[nH]c(=O)[nH]c12
Reaction time: 2 h

Procedure:
3-Methoxyanthranilic acid (6 g, 0.036 mol) was suspended in water (200 ml, 35°) and glacial acetic acid (2.2 ml). A freshly prepared solution of potassium cyanate (3.7 g, 0.046 mol) in water (20 ml) was added dropwise to the stirred mixture. After 2 hours, sodium hydroxide (48.5 g 1.21 mol) was added in portions keeping the temperature below 40°. A clear solution was obtained momentarily before precipitating the hydrated sodium salt. After cooling, the precipitate was filtered off, dissolved in hot water which was acidified to pH 5, causing precipitation of 8-methoxy-2,4-quinazolinedione (4.6 g, 58%) m.p. 255°-257°.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH2:6]([CH:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10](=[O:20])[CH:9]1[CH3:21])[CH3:7].C(Br)C#C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:6]([CH:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:3][C:2]#[CH:1])[C:10](=[O:20])[CH:9]1[CH3:21])[CH3:7]
Reactant: CCC1NC(c2ccccc2)=NC(=O)C1C
Reactant: [Li]CCCC
Agent: C#CCBr
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCN1C(=O)C(C)C(CC)N=C1c1ccccc1
Reaction time: 0.25 h

Procedure:
Oven dried glassware and a nitrogen purge were utilized. 3.22 mL of 1.6 Molar n-butyl lithium in hexanes (5.15 mmol) was added dropwise to a solution of 1.06 g (4.93 mmol) of 6-ethyl-5-methyl-2-phenyl-5,6-dihydropyrimidin-4-one, in 15 mL of dry tetrahydrofuran, at -50 to -60° C. The mixture was stirred for 15 minutes and then 0.8 mL (5.38 mmol) of 80 wt.% propargyl bromide in toluene was added at -65° C. The ice bath was removed after 1.5 hours and the reaction mixture was stirred for an additional 20 hours. The solvent had evaporated overnight. Ether was added and the reaction mixture was washed three times with water followed by three times with 3 Molar hydrochloric acid. The acidic aqueous washes were combined, cooled externally, and 50% sodium hydroxide was added until the pH=10, then extracted three times with ether. The ether extracts were combined, dried over magnesium sulfate, and concentrated to yield 0.68 g of crude product. The crude product was combined with crude product obtained from previous reactions and purified on a six inch plug of basic alumina by washing with 400 mL of methylene chloride. The filtrate was concentrated to yield 6-ethyl-5-methyl-2-phenyl-3-propargyl-5,6-dihydropyrimidin-4-one (Compound 1), as a yellow solid, melting 62°-65° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17].[OH-].[Na+].Br[CH2:34][C:35]([OH:37])=[O:36].Cl>CCO.O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:34][C:35]([OH:37])=[O:36])[CH2:22][CH2:21]1)=[O:17]
Reactant: O=C(O)CBr
Reactant: COc1ccc(C(=O)NCC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)NCC2CCN(CC(=O)O)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
To 1 g 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide hydrochloride and 400 mg NaOH in 50 ml EtOH/H2O 1:1 0.35 g bromo acetic acid were added at RT. After stirring over night the reaction mixture was acidified with half concentrated HCl. After evaporation of the solvent the residue was coevaporated with toluene. The waxy brown solid was subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12](O)=O)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[N:20]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]#[N:20])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: c1ccncc1
Reactant: COc1cccc2sc(C(=O)O)cc12
Agent: CS(=O)(=O)Cl
Product: COc1cccc2sc(C#N)cc12
Reaction time: 2 h
Yield: 74 %

Procedure:
(Ref: Cheutin et al.; C.R. Hebd. Seances Acad. Sci; 261; 1965; 705.) A solution of 4-methoxy-1-benzothiophene-2-carboxylic acid (1.19 g, 5.7 mmol) in pyridine (25 mL) at 0° C. was treated with methanesulfonyl chloride (0.49 mL, 6.3 mmol) keeping the temperature at 0° C., stirring was continued for 2 h. Ammonia gas was then bubbled through the mixture for 5 minutes, followed by nitrogen for 10 mins. The reaction mixture was then treated with a large excess of mesyl chloride (4.43 mL, 57 mmol) and stirred for 16 h at room temperature. The solvent evaporated in vacuo to give a brown residue which was purified by flash chromatography with 10% ethyl acetate in hexane to give a colourless solid (800 mg, 74%); δH (300 MHz, CDCl3) 8.00 (1H, s, 3-ArH), 7.48-7.35 (2H, m, ArH), 6.80-6.77 (1H, m, ArH) and 3.92 (3H, s, OCH3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]3[C:23]([CH2:26][OH:27])=[CH:24][CH:25]=[C:14]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C)C1C=CN=CC=1.C1COCC1>[C:35]([O:27][CH2:26][C:23]1[N:15]2[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:11]3([CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[C:14]2=[CH:25][CH:24]=1)(=[O:37])[CH3:36]
Reactant: OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methanol (1.66 g, 4.60 mmol) and 4-(dimethylamino)pyridine (561 mg, 4.60 mmol) in dry THF (40 mL) was cooled to 0° C. Triethylamine (2.56 mL, 18.4 mmol) was then added to the reaction mixture followed by dropwise addition of acetic anhydride (1.27 mL, 13.5 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. It was then concentrated and purified by column chromatography (silica gel: 10-40% EtOAc in hexanes) to give (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl acetate (1.32 g, 61% yield over two steps). ESI-MS m/z calc. 402.5, found 403.7 (M+1)+; Retention time: 1.31 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(=O)(O)[O-:28].[Na+]>COCCOC.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][OH:28])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(CO)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
A solution of 1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 20 ml 1,2-dimethoxyethane is stirred at room temperature for 3 hours with a solution of 0.47 g of sodium bicarbonate in 10 ml of water. The solvent is evaporated off under reduced pressure and the residue is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purifed by chromatography on a silica gel column using methylene chloride/ethyl acetate (2:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-hydroxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.35 ppm (d, 1H), 5.24 ppm (m, 1H), 4.59 ppm (d, 1H), 4.54 ppm (d, 1H), 3.50 ppm (s, 3H), 2.44 ppm (s, 3H), 2.34 ppm (s, approx. 1H, very broad), 1.36 ppm (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[H-].[Na+].[C:14]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24](SC)[S:25][CH3:26])(=[O:22])=[O:21].O>CN(C)C=O>[C:14]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1)[S:25][CH3:26])(=[O:21])=[O:22]
Reactant: COc1nc(N)nc(OC)n1
Reactant: CSC(=NS(=O)(=O)c1ccccc1-c1ccccc1)SC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 300 ml of dimethylformamide, and 4 g of sodium hydride (oily, 60%) were added to the suspension. The mixture was stirred at room temperature for 1 hour. Furthermore, 33.7 g of dimethyl N-(2-biphenylylsulfonyl)carbonimidodithioate were added, and the mixture was stirred at room temperature for a day and night. The reaction mixture was poured into 2 liters of water and filtered. The filtrate was made weakly acidic to precipitate white crystals. The crystals were collected by filtration and recrystallized from ethanol to give 36.2 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea (compound No. II-1), the same compound as obtained in Example 5. The melting point of the product was 135° to 137° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C)C=CC=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mechanically stirred solution of 1H-Indole-5-carboxylic acid (5-1, 20.01 g, 124 mmol) in THF (500 mL) was added at ambient temperature slowly a solution of 1M-LAH in toluene (186 mL, 186 mmol, 1.5 equiv). The reaction mixture was heated at reflux for 1 h, quenched with ice, partitioned between ethylacetate and saturated aqueous NaHCO3. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude product solidified upon standing under the reduced pressure. The crude solid was suspended in hexanes (200 mL) and ethyl acetate (10 mL), stirred overnight, collected by filtration and air-dried to afford the desired product as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (br s, 1H), 7.62 (s, 1H), 7.36 (d, 1H, J=8.4 Hz), 7.23 (d, 1H, J=8.4 Hz), 7.20 (s, 1H), 6.54 (s, 1H), 4.75 (s, 2H), 1.68 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1ccc(I)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-fluoro-4-iodobenzoic acid (5.00 g, 18.0 mmol), oxalyl chloride (2.0 mL, 22.0 mmol), ammonia gas, DCM (100 mL) and THF (100 mL) to afford 2.00 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.40 (t, J=7.8 Hz, 1H), 7.63-7.76 (m, 1H); MS (m/z): 266.19 (M+H)+.
Reaction SMILES: [C:1]1([C:7](=[NH:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=O.C(=O)(O)[O-].[Na+].O>C1COCC1>[C:1]1([C:7]2[NH:9][CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: N=C(N)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzenecarboximidamide (2.9 g, 24 mmol), 4-bromoacetylbenzonitrile (5 g, 22 mmol), and sodium bicarbonate (1.8 g, 22 mmol) were suspended in 70 mL of THF and 10 mL of water and heated at reflux overnight. The reaction mixture was cooled rt, and partially concentrated. An additional 10 mL of water was added, and the resulting suspension was stirred at 50-60° C. for 30 min. The mixture was cooled with an ice-water bath and the precipitate was collected by filtration, rinsed with two 10-mL portions of water, and air-dried. The solid material was stirred with 15 mL of EtOAc and 15 mL of hexanes, and was again collected by filtration, and dried to give 4-(2-phenyl-1H-imidazol-4-yl)benzonitrile. LCMS: min [M+1]=246.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([F:21])[S:19]Cl.C(SC(F)F)C1C=CC=CC=1.ClCl>ClCCl.N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8](=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)[S:19][CH:18]([F:21])[F:17])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: FC(F)SCl
Reactant: COC(=O)C1SC(=CC(=O)OC(C)(C)C)S1
Agent: ClCl
Agent: FC(F)SCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1SC(=C(SC(F)F)C(=O)OC(C)(C)C)S1

Procedure:
Methyl 2-(t-butoxycarbonylmethylene)-1,3-dithietane-4-carboxylate (1.05 g) is reacted with difluoromethylsulphenyl chloride, which was synthesized from difluoromethyl benzyl thioether (1.74 g) and chlorine, in dichloromethane (5 ml) at room temperature in the presence of pyridine (0.65 ml) until no starting carboxylate is detected in the reaction mixture. The mixture is then washed with a 5% sodium thiosulfate solution and 10% HCl, dried, and concentrated in vacuo to give methyl 2-(1-t-butoxycarbonyl-1-difluoromethylthiomethylene)-1,3-dithietane-4-carboxylate.
Reaction SMILES: O=[C:2]([C:21]1[NH:25][N:24]=[N:23][N:22]=1)[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Cl:14])[C:12]=1[Cl:13])[CH2:9][C:8]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:15])[CH2:7]2.Cl.[NH2:27][OH:28].Cl>N1C=CC=CC=1>[N:27](=[C:2]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Cl:14])[C:12]=1[Cl:13])[CH2:9][C:8]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)([CH3:15])[CH2:7]2)[C:21]1[NH:22][N:23]=[N:24][N:25]=1)[OH:28]
Reactant: NO
Reactant: CC1(C2CCCC2)Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C2CCCC2)Cc2cc(OC(=NO)c3nnn[nH]3)c(Cl)c(Cl)c2C1

Procedure:
A stirred solution of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxymethyl)tetrazole (5.7 g., 0.015 mole) and hydroxylamine hydrochloride (3.2 g., 0.045 mole) in pyridine (60 ml.) is heated at 95°C. on a steam bath for 30 hours then poured into aqueous hydrochloric acid affording 5-(1-hydroximino-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxymethyl)tetrazole.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:63][C:64]1[CH:70]=[C:69]([S:71]([CH3:74])(=[O:73])=[O:72])[CH:68]=[CH:67][C:65]=1[NH2:66]>>[F:63][C:64]1[CH:70]=[C:69]([S:71]([CH3:74])(=[O:72])=[O:73])[CH:68]=[CH:67][C:65]=1[NH:66][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(S(C)(=O)=O)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.36 g, 0.62 mmol), was reacted with diisopropylethylamine (0.64 g, 5 mmol), diphenylphosphinic chloride (0.59 g, 2.5 mmol), then reacted with 2-fluoro-4-(methylsulfonyl)aniline (Matrix) (0.12 g, 0.62 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-fluoro-4-methanesulfonyl-phenyl)-amide as a off white solid (Yield 20 mg, 5%).