Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cn34)ccnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(OCc3nnc4ccc(C5=CCNCC5)cn34)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
tert-Butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.113 g, 0.23 mmol) was dissolved in methanol (3 mL) then added concentrated hydrochloric acid (0.500 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The remaining solid was suspended in methanol (1 mL) then added triethylamine (0.40 ml, 2.9 mmol). The clear solution was stirred at room temperature for 2 hours then concentrated under vacuum. The sample was purified by flash chromatography eluting with 8% 7N ammonia in methanol/dichloromethane to afford 7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (0.038 g, 42% yield) as a tan solid. MS (ESI pos. ion) m/z: 388.1 (MH+).
Reaction SMILES: [ClH:1].[CH2:2]1[CH2:7][CH2:6][C:5]2([CH2:12][NH:11][C:9](=[O:10])[CH2:8]2)[CH2:4][CH2:3]1.[OH2:13]>>[ClH:1].[NH2:11][CH2:12][C:5]1([CH2:8][C:9]([OH:13])=[O:10])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CC2(CCCCC2)CN1
Reactant: O
Agent: Cl
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 108 °C
Yield: 60 %

Procedure:
22.3 L of water and 22.3 L of concentrated hydrochloric acid are mixed in a T100 reactor and 6.41 kg gabapentin lactam added while stirring. The clear brown solution formed is subsequently boiled under reflux at 108° C. for 6 hours. The reaction mixture is then left until it has cooled to 28° C. The white precipitate obtained is again dissolved by the addition of a further 40 L of water. For the removal of still undissolved lactam, the reaction mixture is extracted three times with, in each case, 30 L of dichloromethane. The pale yellow aqueous phase is evaporated to dryness in a vacuum evaporator (QVF 100L). At 133 Pa, the temperature finally reached 80° C. The almost dry crystal mass is stirred up with 12.8 L of acetone and sucked off. It is then washed with 2 L of acetone and dried for 4 hours at 60° C. The yield is about 60% of theory.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=2)[C:13](=[O:27])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.CC(O)=O.[Pd]>[O:27]=[C:13]1[CH2:12][NH:11][CH2:16][CH2:15][N:14]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=[NH:25])=[CH:20][CH:19]=1
Reactant: N=C(N)c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1ccc(CN2CCNCC2=O)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(4-carbamimidoylbenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (2.0 g, 5.0 mmol) in 40 mL of MeOH and 4 mL of AcOH is added 10% Pd/C (0.4 g). The atmosphere above the reaction is replaced by hydrogen. After 4 hours, the solution is filtered through a pad of Celite. The organic layer is concentrated. The resulting crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1%TFA) to 40% CH3CN/H2O (0.1% TFA). The title compound is obtained as a white foam. 1H NMR (d6-DMSO, 300 MHz) δ9.3 (bs, 4H), 9.1 (bs, 2H), 7.83 (d, 2H), 7.42 (d, 2H), 4.78 (s, 2H), 3.80 (s, 2H), 3.44 (m, 2H), 3.32 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br-].[CH2:19]([C:21]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)([C:24]1[S:25][CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:22][CH3:23])[CH3:20].C1COCC1>C1COCC1.CCOC(C)=O>[CH2:19]([C:21]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[CH3:1])=[C:32]([CH3:37])[CH:31]=1)([C:24]1[S:25][CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CC(=O)C(C)(C)C
Reactant: CCC(CC)(c1ccc(C)c(C)c1)c1cc(C)cs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(CCC(=O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a 0° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanol (6 g,) in THF (50 ml) is treated with PBr3 (2.2 ml, 23.3 mmol) and warmed to RT. After stirring for 2 h, the mixture is partitioned between EtOAc and brine. The organic layer is MgSO4 dried, concentrated, and dissolved in anhydrous THF (30 ml) to give a solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methane bromide. Separately, a solution of 3,3-dimethyl-butan-2-one (5.3 ml, 42.4 mmol) in THF (15 ml) is treated with LiHMDS (42.4 ml, 42.4 mmol, 1M in THF) at −70° C. for 1 h. This solution is transferred (via cannula) into a −70° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanebromide/THF. The mixture is warmed to RT and stirred for 1 h. The reaction is diluted with EtOAc and washed with 0.2 N HCl until the aq layer is pH 2. The organic layer is concentrated to give the title compound (6.2 g, 79%).
Reaction SMILES: C([NH:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)(=O)C.[CH3:19][NH:20][CH3:21].O>C(O)(=O)C>[NH2:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:20]([CH3:21])[CH3:19]
Reactant: CNC
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCC1CO1
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.085 mol (21.5 g) of 1-(2'-acetylamino-4'-nitrophenoxy)-2,3-epoxypropane (compound described in Example (4) is introduced into 100 ml of a 40% strength aqueous solution of dimethylamine, and the reaction mixture is stirred for 30 minutes at ambient temperature. After dilution by the addition of 225 ml of iced water, followed by neutralisation with acetic acid, the mixture is evaporated to dryness in vacuo. The dried residue is taken up in 150 ml of ethyl acetate. After washing with acetone, the material which is insoluble in ethyl acetate consists of 28.5 g of 1-(2'-acetylamino-4'-nitrophenoxy)-3-dimethylaminopropan-2-ol. This acetylated derivative is heated under reflux for two hours in 220 ml of ethanol saturated with hydrogen chloride. After the reaction medium has cooled, the expected product in the form of the hydrochloride is filtered off. After this hydrochloride has been dissolved in water and the aqueous solution has been rendered alkaline with sodium hydroxide solution, the 1-(2'-amino-4' -nitrophenoxy)-3-dimethylaminopropan-2-ol is precipitated in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH3:38][CH:39]([CH3:44])[CH2:40][C:41](Cl)=[O:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:41](=[O:42])[CH2:40][CH:39]([CH3:44])[CH3:38])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: CC(C)CC(=O)Cl
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)CC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoate (prepared in Step A of Example 47), but using 3-methylbutanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([C:35]([OH:37])=[O:36])[N:34]=2)[N:31]=1>>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([N:32]=[C:33]([C:35]([OH:37])=[O:36])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)c1nc2ccc(Cl)nn2n1
Product: O=C(O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Yield: 34.2 %

Procedure:
2.33 g of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 714 mg of (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-2-yl)carboxylic acid were stirred at 175° C. for 30 minutes. After cooling, the reaction mixture was crystallized by the addition of water-ethyl acetate-ethanol (2:2:1), collected by filtration, washed with water-ethyl acetate-ethyl ether (2:1:2) and dried to yield 598 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[CH:30]([O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:30]([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 24 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-methoxyphenyl)indole-3-carboxylic acid ethyl ester (153 mg, 0.40 mmol and 4-isopropoxyphenylboronic acid (108 mg, 0.60 mmol). Yield 111 mg, 52%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6](=[O:15])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O.[NH2:16][C:17](=[S:30])[C:18]([CH3:29])([CH3:28])[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CO>[CH3:29][C:18]([C:17]1[S:30][CH:2]=[C:3]([C:5]2[C:6](=[O:15])[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:16]=1)([S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH3:28]
Reactant: O=C(CBr)c1cc2ccccc2[nH]c1=O
Reactant: CC(C)(C(N)=S)S(=O)(=O)c1ccccc1
Solvent: CO
Product: CC(C)(c1nc(-c2cc3ccccc3[nH]c2=O)cs1)S(=O)(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3-(2-bromoacetyl)-1h-quinolin-2-one (Example 27(b), 270 mg, 1.0 mmol) and 2-amino-1,1-dimethyl-1-(phenylsulfonyl)ethane-2-thione (step b, 1.7 ml, 1.0 mmol) in 3.5 ml of anhydrous MeOH was heated at 120° C. for 5 min by microwave synthesizer. The reaction mixture was cooled to RT. The precipitates were collected by filtration and washed with MeOH and CH2Cl2 to provide the title compound as a light yellow solid. Ms m/z: 411.3 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([C:31]([F:39])([F:40])[F:30])=[CH:33][CH:34]=3)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c(-c3ccccc3)c2)=C(C)C1=O
Reaction time: 16 h
Yield: 36.5 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (16 mg, 0.0408 mmol) was dissolved in methylene chloride (3 ml), then 4-trifluoromethylaniline (13 mg, 0.0807 mmol), triethylamine (8.2 mg, 0.0811 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (21 mg, 0.1242 mmol) were added thereto and the mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (8 mg, 0.0149 mmol, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=2)[C@@H:9]1[CH:20]([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1C=C2C(C)N(C(OC(C)(C)C)=O)[C@@H](C(C)C)C2=NC=1>>[C:1]([O:5][C:6]([N:8]1[CH:16]([CH3:24])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=2)[C@@H:9]1[CH:20]([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1c2ncc(Cl)cc2C(C)N1C(=O)OC(C)(C)C
Reactant: CC(C)[C@H]1c2ncc(C(=O)O)cc2CN1C(=O)OC(C)(C)C
Product: CC(C)[C@H]1c2ncc(C(=O)O)cc2C(C)N1C(=O)OC(C)(C)C
Reaction time: 0.02 h

Procedure:
Procedure same as that for (S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid, using tert-butyl(7S)-3-chloro-7-isopropyl-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as a starting material. LC-MS tR=0.99 min in 1 min chromatography, MS (ESI) m/z 321.5 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C@:23]12[CH2:30][C@H:27]([NH:28][CH2:29]1)[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][C@:23]4([CH3:22])[CH2:30][C@H:27]3[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)C[C@@H]2C[C@@](C)(CN2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@@H]2C[C@@](C)(CN2C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane hydrochloride (380228-03-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=420.2 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][O:10][CH3:9])=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCCOc1ccc(Br)cc1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
4-Bromophenol (8.65 g; 0.05 mol), 2-methoxyethanol (1.1 eq.; 0.055 mol; 4.36 ml) and triphenylphosphine (1.1 eq.; 0.055 mol; 14.4 g) are dissolved in 210 ml of toluene. The reaction medium is brought to 54° C. and diisopropyl azodicarboxylate (1.0 eq.; 0.05 mol; 10.1 g) dissolved in 21 ml of toluene is added dropwise. The reaction medium is left at 54° C. for one hour and then overnight at room temperature, and is then evaporated to dryness. The crude product is purified by flash chromatography on silica on a gradient of heptane comprising 0-100% DCM to give 9.6 g of the expected product in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:24])[CH3:23].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:22]([NH:24][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19])[CH3:23]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜30 mL, ˜34.5 mmol) was added 2.0M ethylamine in THF (34.5 mL, 69 mmol) and T3P (50% solution in EtOAc, 33 ml, 51.8 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75M Biotage™ column, eluting with a gradient of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (4.0 g, 35% yield). Rf=0.40 (15% MeOH/CH2Cl2+0.2% NH4OH), LRMS m/z Calcd for C18H25ClN2O2, 336.9, found, 337.4 (M+H) APCI; 1H-NMR (CDCl3) δ 7.54 (dd, J=8.3, 2.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (d, J=7.9 Hz, 1H), 6.52-6.35 (br m, 1H), 3.86 (s, 2H), 3.29-3.22 (m, 2H), 2.81-2.60 (m, 7H), 2.48 (d, J=8.3 Hz, 2H), 1.83 (br s, 4H), 1.11 (dt, J=7.3, 2.9 Hz, 3H); 13C-NMR (CDCl3) δ 176.7, 147.0, 134.2, 133.3, 131.4, 126.5, 123.8, 73.8, 73.9, 56.1, 54.1, 41.2, 35.0, 33.0, 23.6, 14.9.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9](O)=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][CH2:9][CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:12])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Cc1ccccc1OCC(=O)O
Product: Cc1ccccc1OCCNC1CC1

Procedure:
Synthesized according to typical procedures C and D from o-tolyloxyacetic acid and cyclopropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:12][C:13]1[CH:14]=[C:15]([C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (10.6 g, 54 mmols), tert-butyl(1R)-1-(3-hydroxyphenyl)ethylcarbamate (13.7 g, 58 mmols), potassium carbonate (8.7 g, 63 mmols) and N,N-dimethylformamide (150 ml) was stirred at 100° C. for 1 hour. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography, and the resulting crystal was re-crystallized from hexane/ethyl acetate to give a crystal of tert-butyl(1R)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (12.9 g, 60%).
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:38][CH:37]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27]CC2C=CC=CC=2)=[O:26])=[O:21])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:40][CH:41]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
A solution of benzyl (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate (1.8 g. 2.77 mmol) in ethyl acetate (30 mL) is hydrogenated in a Parr shaker in the presence of palladium on carbon (10%, 800 mg) at 40 psi for 4 hours. The catalyst is filtered off and washed with methanol (30 mL). After concentration of the filtrate in vacuo, the residue is triturated with ether and the resulting crystalline solid dried under reduced pressure to give (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)propionyl]-3-aminopropionic acid. It is recrystallized to constant melting point from methanol/ether, m.p. 102°; [α]D =-8.99 (c=0.95, CH3OH).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[CH3:43][C:44]1[CH:48]=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[NH:46][N:45]=1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:45]2[C:44]([CH3:43])=[CH:48][C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N:46]2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CCOC(=O)c1cc(C)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 3-methyl-1H-pyrazole-5-carboxylate. The regioisomers were separated by silica gel chromatography. Compound 28: M/e+ 395 for C21H20ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.24 (d, J=6.9 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.17 (td, J=6.6, 1.1 Hz, 1H), 6.78 (td, J=6.6, 1.1 Hz, 1H), 6.50 (s, 1H), 6.01 (s, 2H), 4.30 (q, J=7.3 Hz, 2H), 2.26 (s, 3H), 1.30 (q, J=7.3 Hz, 3H) ppm; Compound 29: M/e+ 395 for C21H20ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.63 (m, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.24 (t, J=6.6 Hz, 1H), 6.84 (t, J=6.6 Hz, 1H), 6.44 (s, 1H), 5.84 (s, 2H), 4.36 (q, J=7.3 Hz, 2H), 1.73 (s, 3H), 1.37 (t, J=3H) ppm.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[CH:7]=1)(=O)C.[CH3:18][S:19]([O-:21])=[O:20].[Na+]>CC(C)=O.O>[CH3:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([CH2:5][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:7]1
Reactant: CC(=O)OCc1cn(C)c2ccccc2c1=O
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21

Procedure:
To a solution of 3-acetoxymethyl-1-methyl-4-quinolone (0.8 g.) in acetone (15 ml.) was added a solution of sodium methanesulphinate (0.53 g.) in water (10 ml.). The mixture was boiled under reflux for 24 hours. Further sodium methanesulphinate (0.14 g.) was added and the mixture was boiled under reflux for 4 hours. Acetone was evaporated from the mixture, causing the separation of a white solid which was recrystallised from industrial methylated spirit to give 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 195°-197°.