Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH2:39][C:40]1[O:41][C:42]([CH3:46])=[C:43]([CH3:45])[CH:44]=1>CN(C)C=O.C(Cl)Cl>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH2:39][C:40]1[O:41][C:42]([CH3:46])=[C:43]([CH3:45])[C:44]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: Cc1cc(Cc2ccc3ccccc3c2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc4ccccc4c3)oc(C)c2C)cc1C(C)C
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (0.93 g, 3.95 mmol, RN-117439-59-5), oxalyl chloride (0.377 mL, 4.33 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.507 mL, 4.33 mmol) and 2-naphthalen-2-ylmethyl-4,5-dimethylfuran (0.93 g, 3.94 inmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2 & 4% EtOAc/pet. ether step gradient gave 0.357 g (20%) of the title compound. 1H NMR (DMSO-d6) δ 1.14 (d, 12 H), 1.82 (s, 3 H), 2.20 (s, 3 H), 3.27 (septet, 2 H), 3.74 (s, 3 H), 4.02 (s, 2 H), 7.19 (dd, 1 H), 7.45-7.52 (m, 5 H), 7.76-7.79 (m, 3 H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:5]=2[O:4][CH2:3]1.[CH3:16][CH:17]([C:21]([NH:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[O:22])[C:18](O)=[O:19]>>[Cl:15][C:14]1[C:5]2[O:4][CH2:3][C@H:2]([NH:1][C:18](=[O:19])[CH:17]([CH3:16])[C:21]([NH:23][CH2:24][C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])=[O:22])[C:8](=[O:9])[N:7]([CH3:10])[C:6]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)COc2c(Cl)cccc21
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1COc2c(Cl)cccc2N(C)C1=O

Procedure:
The title compounds were obtained according to the procedure described in example 2b) by condensation of (S)-7-amino-4-chloro-9-methyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one with 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid (ex 1c).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26]CC)=O)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([NH:30][NH2:31])=[O:26])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of 4-benzyl-1-(2-(3-(ethoxycarbonylmethyl)phenoxy)ethyl)piperidine (0.382 g, 1.00 mmol) in 5 mL of MeOH was added 5 mL of hydrazine hydrate. The resulting solution was allowed to stir at rt for 12 hr. The MeOH was evaporated in vacuo and water (10 mL) was added. A colorless solid precipitated. The solid was collected by filtration and dried in vacuo giving the title product (240 mg, 65%): mp 89-91° C.; 1H NMR (CDCl3) 1.31 (m, 2 H), 1.60 (m, 1 H), 1.62 (m, 2 H), 2.04 (t, J=11.7 Hz, 2 H), 2.52 (d, J=6.9 Hz, 2 H), 2.76 (t, J=6.0 Hz, 2 H), 2.95 (d, J=11.4 Hz, 2 H), 3.53 (s, 2 H), 3.83 (bs, 2 H), 4.08 (t, J=6.3 Hz, 2 H), 6.66 (s, 1 H), 6.79 (m, 3 H), 7.12-7.27 (m, 6 H).
Reaction SMILES: [C:1]([C:5]1[CH:48]=[CH:47][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=4)=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([NH:15][CH2:16][C:17](O)=[O:18])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][CH:38]=4)=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([NH:15][CH2:16][C:17]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:18])=[O:14])=[O:10])=[CH:47][CH:48]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(N)(=O)=O
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)O)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)NS(C)(=O)=O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
TEA (32.1 μl, 0.23 mmol) was added to a suspension of (S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine Compound 297 (75.0 mg, 0.11 mmol), methanesulfonamide (12.1 mg, 0.13 mmol), HATU (52.6 mg, 0.14 mmol) and DMAP (1.41 mg, 0.01 mmol) in DCM (2 mL). The resultant yellow suspension was stirred at room temperature for 3 h. The reaction mixture was washed with saturated aqueous NaHCO3 (2 mL) and the mixture passed through a phase separation cartridge. The organic phase was concentrated in vacuo to afford a yellow solid. The crude product was purified by chromatography (EA/1% AcOH in hexanes) to afford 9 mg (11%) (S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide, Compound 381 as a yellow solid. LCMS-ESI (m/z) calculated for C40H49N5O6S: 727.3. found 728.0 [M+H]+, tR=10.51 min (Method 10).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:15]([O-])=O)=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[NH2:15][C:12]1[N:11]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]2=[N:14][CH:13]=1
Reactant: CCOC(=O)c1cccc2ncc([N+](=O)[O-])n12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc2ncc(N)n12
Temperature: 25 °C
Reaction time: 110 h
Yield: 43.5 %

Procedure:
To a solution of 2.35 g of 5-ethoxycarbonyl-3-nitroimidazo[1,2-a]pyridine in 100 ml of ethanol was added 10% Pd—C (wet, 470 mg). The mixture was stirred for 110 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with ethanol. The filtrate and the washing were combined, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to afford 891 mg of the desired compound (43.4%, a dark reddish oil).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2
Reactant: Oc1cccc2ncccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2nccc(Oc3cccc4ncccc34)c2cc1OC
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (50 mg) and commercially available 5-hydroxyquinoline (50 mg) were mixed and stirred at 170° C. for 10 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting first with hexane/ethyl acetate (1/1) and then with chloroform/methanol (50/1) to obtain 47 mg of the title compound (yield: 64%).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.F[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37]>>[CH:35]1([CH:36]([OH:37])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:34]1
Reactant: O=Cc1ccccc1F
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (10 g) and 2-fluorobenzaldehyde (2.6 cc), 4-dimethylamino-1-(2-fluorophenyl)-2-phenyl-2-buten-1-ol (Z) hydrochloride (3.5 g) is obtained in the form of a white powder melting at 175° C. after recrystallisation from a mixture (90 cc) of isopropanol and isopropyl ether (60/40 by volume).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:23]1[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
2-chloro-5-nitrobenzaldehyde (1.03 g, 5.39 mmol) was dissolved in dichloromethane (20 mL), and added with tert-butyl-piperazine-1-carboxylate (1 g, 5.39 mmol). The reaction solution was cooled to 0° C., and slowly added with NaBH(OAc)3 (1.6 g, 7.55 mmol), followed by stirring for 3 hours at room temperature. The reaction mixture was added with water, and subjected to extraction with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:7 (v/v)) to obtain the title compound (1.9 g, 99%).
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[NH2:16][CH2:17][CH2:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>ClCCl>[NH2:16][CH2:17][CH2:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([F:7])=[O:22]
Reactant: NCCc1nc(Cl)ccc1C(=O)O
Reactant: FC1=CC(F)=NN(F)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NCCc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 5.0 g (24.8 mmol) of 2-(aminoethyl)-6-chloronicotinic acid in 125 ml of dichloromethane. The mixture is stirred for 3 hours at ambient temperature and then filtered. The solid is rinsed with 50 ml of dichloromethane and the filtrate is washed twice with 60 ml of ice-cold water. The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 5.01 g of product are obtained in the form of an orange oil. Yield=99%.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:22])[CH2:20][CH3:21])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: CCC(=O)Cl
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCC(=O)Nc1nc(-c2ccccc2)c(-c2nc(C)no2)s1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and propionyl chloride.
Reaction SMILES: [C:1]1([CH:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:38]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CO
Product: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of N-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea (300 mg, 0.51 mmol) (Preparation 4) in methanol (150 ml) was treated with aqueous hydrochloric acid (2M, 100 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent volume was then reduced to 100 ml by evaporation under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution (50 ml) and ethyl acetate (200 ml) were added. The two phases were separated. The organic layer was washed with saturated aqueous sodium chloride solution (100 ml), dried (anhydrous magnesium sulphate) and evaporated to give the title compound as a solid (255 mg).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH:31](O)(C)C>[Ni]>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:11]3[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=3[N:19]=[CH:31]2)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(OC(C)=O)C1OC(C)=O
Reactant: CC(C)O
Agent: [Ni]
Product: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (2.75 g, 5.93 mmol) and Raney nickel (aqueous slurry, Aldrich, 300 mg wet) in isopropanol (250 mL) was shaken under hydrogen (40 psi) in a Parr shaker for 2.25 hours. Catalyst was filtered off with Celite and the filtrate acidified with 98% formic acid (5 mL) and concentrated to an orange oil. The oil was diluted with additional 98% formic acid (45 mL) and the resulting orange solution refluxed for 40 minutes. Volatiles were removed and the remaining dark oil dissolved in chloroform (100 mL). The chloroform solution was washed with saturated aqueous sodium bicarbonate (3×10 mL), dried (sodium sulfate), and evaporated to a foam which was chromatographed on silica gel. Title compound eluted with methanol:chloroform/3:97 as a white foam from ethyl acetate (2.26 g, 86%); 1H-NMR (DMSO-d6)δ: 8.57, 8.17, 7.97 (all s, 1 each, 3 benzimidazole CH), 5.6 (m, 1, CHO), 5.3-5.1 (m, 2, CHO and CHN), 4.35-4.15 (m, 2, CH2O), 2.6-2.4 (m overlapping solvent, 2 CH), 2.10, 2.06, 1.92 (all s) overlapped by 2.0 (m, total 10, 3CH3CO and CH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.Cl.CC(O)C>C(OCC)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C@:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(c1cc(Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)ccc21

Procedure:
0.10 g (0.40 mmol) (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL 2-propanol and the mixture was refluxed for 4 h. Then the reaction mixture was diluted with diethyl ether, suction filtered and washed with diethyl ether. The precipitate was dissolved in DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14](OCC)=[O:15])=[CH:10][CH:9]=2)[O:5][C:4](=[O:21])[C:3]=1[S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH4-].[Li+]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:19][CH:20]=2)[O:5][C:4](=[O:21])[C:3]=1[S:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCO)cc2)cc(O)c1SCCc1ccccc1
Reaction time: 8 h

Procedure:
To a tetrahydrofuran (7 mL) solution of [4-[4-hydroxy-2-oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-phenoxy]acetic acid, ethyl ester (0.30 g, 0.70 mmol) was added 2.0M lithium borohydride (0.5 mL, 1.00 mmol). The reaction was stirred overnight. The reaction was then quenched by addition of 1N hydrochloric acid (2.0 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated and washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel--230 to 400 mesh) using 50% ethyl acetate/hexanes to 100% ethyl acetate as the eluent. m.p. 123°-125° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2H), 2.97 (t, 2H), 3.37 (m, 2H), 4.07 (t, 2H), 4.92 (bs, 1H), 6.68 (s, 1H), 7.09 (d, 2H), 7.19 (m, 5H), 7.75 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([C:21]2[CH:25]=[C:24]([C:26](=O)[CH3:27])[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:26]([C:24]2[O:23][N:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=2)[CH3:27])=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(-c2ccccc2)no1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc(-c2ccccc2)no1

Procedure:
Prepared according to the procedure described in Example 2, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-(3-phenyl-isoxazol-5-yl)-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])N.[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(N)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(O)cc1Cl
Yield: 30 %

Procedure:
To a 0° C. solution of 3-chloro-4-methoxy aniline (1.0 g; 6.4 mmol) in 1:1H2O:conc. H2SO4 (100 mL) was added very slowly a solution of NaNO2 (0.5 g; 7.6 mmol) in H2O (10 mL). Thick yellow fumes were emitted, and the black solution was then heated to reflux for 30 min. The mixture was extracted with EtOAc (4×50 mL) and the combined extracts were concentrated in vacuo. The residue was chromatographed (SiO2; 4:1 hex:EtOAc) to obtain 3-chloro-4-methoxy phenol (300 mg; 30%) as a yellow oil.
Reaction SMILES: [Cl:1]C1SC=C(C2C(=O)NC(=O)NC2=O)C=1.Cl[C:17]1[S:21][CH:20]=[C:19]([CH:22]2[O:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])[CH:18]=1>>[Cl:1][C:20]1[S:21][CH:17]=[CH:18][C:19]=1[CH:22]1[O:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: O=C1NC(=O)C(c2csc(Cl)c2)O1
Reactant: O=C1NC(=O)C(c2csc(Cl)c2)C(=O)N1
Product: O=C1NC(=O)C(c2ccsc2Cl)O1

Procedure:
The same procedure is employed to convert 5-(5-chloro-3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione to 5-(5-chloro-3-thienyl)oxazolidine-2,4-dione.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][OH:16])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: NCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CCNCCO)cc1

Procedure:
A mixture of 1-(2-Bromoethyl)-4-nitrobenzene (5.0 g, 22 mmol), 2-aminoethanol (1.7 g, 28 mmol), and triethylamine (6.6 mL, 48 mmol) was heated to 60° C. for 16 hours in DMF. LC showed formation of the desired product. DMF was removed under reduced pressure, and the residue was dissolved in EtOAc. The desired product was precipitated out with hexanes. LC-MS (IE, m/z): 211 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[CH:32][C:31]=1[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:31]4[CH:32]=[C:33]5[N:34]([N:30]=4)[CH:35]=[CH:36][CH:37]=[CH:38]5)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1cc2ccccn2n1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc3ccccn3n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and pyrazolo[1,5-a]pyridine-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:16]=[N:15]2)[N:3]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc(-c2ccccc2C)cn1
Product: Cc1ccccc1-c1cnn(CCC#Cc2cccc(CF)n2)c1
Yield: 30000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.26 mmol) and 1-but-3-ynyl-4-o-tolyl-1H-pyrazole (50 mg, 0.24 mmol, Example 142(A)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (72 mmol, 30%) of 2-(fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid with a purity of 81%.