Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[C:18]([O:22][C:23]([NH:25][C@H:26]([C:37](O)=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:37](=[O:38])[C@H:26]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:24]
Reactant: NCCCCCCCO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCCCCCCO

Procedure:
N-Methylmorpholine (2.2 mL, 19.7 mmol) was added dropwise at room temperature to 7-amino-1-heptanol hydrochloride salt (3.3 g, 19.7 mmol), in 50 mL of dry DMF under argon with stirring. After stirring for 5 minutes the following were added: N-t-butoxycarbonyl-L-tryptophan, (5 g, 16.45 mmol), 1-hydroxybenzotriazole, (2.52 g, 16.45 mmol) and EDCI hydrochloride (4.73 g, 24.7 mmol). The mixture was stirred for 2 hours and then the DMF removed under reduced pressure. The residue was taken up in cold 2.5% HCl (100 mL) and ethyl acetate (3×100 mL) and transferred to a separatory funnel. The organic phase was isolated and washed consecutively with cold 2.5% HCl (100 mL) and then brine (100 mL). The ethyl acetate phase was dried (MgSO4), filtered and concentrated to obtain N-t-butoxycarbonyl-L-tryptophan-(7-hydroxyheptyl)amide; IR (neat): 3300, 2921, 1685, 1645, 1490, 1356, 1157 cm-1 ; 1H NMR (80 MHz, CDCl3): δ 0.98-1.62 (m, 10H, --(CH2)5 --), 1.45 (s, 9H, t-butyl), 2.86-3.32 (m, 4H,CH--CH2, HN--CH2), 3.68 (t, 2H, J=5.6 Hz, --CH2OH), 4.22-4.55 (m, 1H, CH), 5.12-5.32 (broad d, 1H, NH--CH), 5.65-5.9 (broad t, 1H, NH--CH2), 6.98-7.92 (m, 5H, ArH), 8.63 (broad 8, indole NH).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]#[N:22])=[CH:10][C:9]=2[CH3:23])=[O:4].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:21]([C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:23])[CH:10]=1)[N:7]=[C:6]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:22]
Reactant: C1CCNCC1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(C#N)cc2c1-c1ccccc1
Product: Cc1cc(C#N)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCCCC3)nc12

Procedure:
The title compound was prepared in analogy to example 21 step D from 2-chloro-6-cyano-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester and piperidine. Yellow solid. MS (ESI): 372.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[O:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=2)=[CH:23]1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:34](=[O:35])[CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:24]4[CH:25]=[CH:26][O:22][CH:23]=4)[CH:28]=3)[CH2:17]2)=[O:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(O)Cc1cccc(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)C1CCCNC1
Agent: Cl
Product: COC(=O)c1cc(Cl)ccc1NC(=O)C1CCCN(C(=O)Cc2cccc(-c3ccoc3)c2)C1

Procedure:
Using the same method as in Example 9-(ii), the target methyl 5-chloro-2-{[(1-{[3-(furan-3-yl)phenyl]carbonyl}piperidin-3-yl)carbonyl]amino}benzoate was quantitatively obtained using the methyl 5-chloro-2-[(piperidin-3-ylcarbonyl)amino]benzoate hydrochloride obtained in Example 11-(ii) and [3-(furan-3-yl)phenyl]acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:5]=[C:4]([OH:18])[CH:3]=1.Cl[C:20]([S:22]Cl)=[O:21]>O1CCCC1>[NH2:1][C:2]1[C:3]2[S:22][C:20](=[O:21])[O:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1
Reactant: Nc1cc(O)nc(SCc2cccc(F)c2F)n1
Reactant: O=C(Cl)SCl
Solvent: C1CCOC1
Product: Nc1nc(SCc2cccc(F)c2F)nc2oc(=O)sc12
Reaction time: 0.67 h
Yield: 97.1 %

Procedure:
To a stirred suspension of 6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol (9.58 g) in tetrahydrofuran (96 ml) was added chlorocarbonylsulfenyl chloride (4.89 g) over 7 minutes, followed by tetrahydrofuran (2 ml). The reaction mixture was stirred for 40 minutes and the resulting precipitate collected by filtration, washing twice with tetrahydrofuran (19 ml), to afford the title compound as a pale yellow solid (11.31 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[P:29](Cl)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>O1CCCC1>[C:9]1([P:8]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[P:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOP(Cl)OCC
Reactant: Brc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Solvent: C1CCOC1
Product: CCOP(OCC)c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Into a four-neck flask was weighed 10.00 g (22.7 mmol) of (2-bromophenyl)[di(1-naphthyl)]phosphine (6). The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 100 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 14.8 mL (23.8 mmol) of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was cooled to −78° C. and thereto was added dropwise a 10 mL THF solution of 3.92 g (23.8 mmol) of diethyl chlorophosphite (manufactured by Aldrich) over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 15 hours. After the completion of the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate={fraction (4/1)}) to obtain the title compound (8.83 g, a pale yellow solid). Yield 81.0%.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.N1CCCCC1>CCO>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:1][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: NS(=O)(=O)c1ccc(-c2ccc(C=O)o2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)cc1
Temperature: 70 °C

Procedure:
To 4-(5-formylfuran-2-yl)benzenesulfonamide (30 mg, 0.120 mmol) in EtOH was added 5-chlorooxindole (20 mg, 0.120 mmol) and piperidine (12 μL, 0.120 mmol). The mixture was stirred at 70° C. for several hours. The solid formed was isolated by filtration and air dried to yield 4-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzenesulfonamide. LC-MS (M+1=401).
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[C:10]([F:11])=[CH:9][N:8]=[C:7]([OH:12])[CH:6]=1>C(Cl)Cl>[Br:4][C:5]1[C:10]([F:11])=[CH:9][N:8]=[C:7]([O:12][CH2:1][CH3:2])[CH:6]=1
Reactant: CCI
Reactant: Oc1cc(Br)c(F)cn1
Solvent: ClCCl
Product: CCOc1cc(Br)c(F)cn1
Temperature: 25 °C

Procedure:
2.08 mL (26.0 mmol) Ethyliodide and 1.08 g (3.91 mmol) Ag2CO3 are added to a mixture of 500 mg (2.160 mmol) 4-bromo-5-fluoro-pyridin-2-ol in 10 mL DCM. The mixture is stirred at r.t. over night. Then the reaction mixture is quenched by the addition of water and DCM. After filtration the org. layer is separated, dried with Na2SO4 and the solvent is removed in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[C@H:10](N)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C1C=C(OC)C(OC)=C(OC)C=1)=C=[O:30].CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([OH:30])[C@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](N2CCC(Cc3ccc(Cl)cc3)CC2)C1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCC(Cc3ccc(Cl)cc3)CC2)C1

Procedure:
Following General Procedure C, (±)-trans-3-amino-4-[4-(4-chlorobenzyl)piperidin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (394 mg, ˜0.9 mmol) and 5-isocyanato-1,2,3-trimethoxybenzene (250 mg, 1.2 mmol) were coupled in CH2Cl2 (6.0 mL) at 0° C. for 1 h. Chromatography of the crude product with 1:1 hexanes:EtOAc to 100% EtOAc gave the product (445 mg, 77% from (±)-trans-3-[4-(4-chlorobenzyl)piperidin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester) as a white solid: mp 99.0-102.5° C.; IR 3371 (br), 2932, 1655, 1607, 1552, 1507 cm−1; 1H NMR δ 1.17-1.80 (m, 14H), 2.18 (m, 2H), 2.48 (d, J=7.0 Hz, 2H), 2.95-3.51 (m, 8H), 3.81 (m, 9H), 4.32 (br, 1H), 5.30 (br, 1H), 6.61 (s, 2H), 7.02 (m, 2H), 7.20 (m, 2H); MS m/z 603.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([S:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21](O)=[O:22])=[CH:14][CH:15]=3)[N:10]3[CH:27]=[N:28][N:29]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:36][N:37](C=O)[CH3:38].CNC>C(Cl)Cl>[CH3:36][N:37]([CH3:38])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([S:17][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]4[N:10]3[CH:27]=[N:28][N:29]=4)=[CH:15][CH:14]=2)[CH:19]=1
Reactant: O=C(O)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nncn4c3c2)c1
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nncn4c3c2)c1
Temperature: 25 °C

Procedure:
To 11a (219 mg, 0.67 mmol) in CH2Cl2 (30 mL) was added oxalyl chloride (0.07 mL, 0.80 mmol) and a drop of DMF. The mixture was then concentrated, and the residue was redissolved in CH2Cl2 and divided into 5 portions. To one portion, dimethylamine (2.0M, 0.3 mL, 0.54 mmol) was added, and the mixture was stirred at room temperature until no SM was observed by LCMS analysis. The reaction was concentrated and purified by preparative HPLC to give the desired product, 11b.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:24]=4)=[CH:21][N:22]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[C:29]1([C:25]2[CH:24]=[C:23]([C:20]3[N:17]4[CH:18]=[CH:19][C:14]([C:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=5)=[CH:15][C:16]4=[N:22][CH:21]=3)[CH:28]=[CH:27][N:26]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C1=C(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Ex. 1.103) (1.0 eq, 0.2 mmol, 90 mg) is dissolved in dioxane/MeOH (1 ml, 1 ml) and HCl (4M in dioxane, 10.0 eq, 2.0 mmol, 0.5 ml) is added. The reaction is stirred at room temperature for 16 h. The solvent is removed in vacuo to yield 3-(2-phenyl-pyridin-4-yl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=353
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: SC1=Nc2ccc(Cl)c3cccc1c23
Reactant: NCCCCCn1ccnc1
Solvent: CCO
Product: Clc1ccc2c3c(cccc13)C(NCCCCCn1ccnc1)=N2
Yield: 76.8 %

Procedure:
A mixture of 4.4 g of 6-chloro-benz[cd]indole-2-thiol, 3.06 g of 5-(1H-imidazol-1-yl)pentanamine, 6.3 g of mercuric acetate and 150 ml of ethanol was reacted as described in Example 1, giving 5.2 g of the desired product, mp 132°-134° C.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:28]=[CH:27][C:20]3[S:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:28]=[CH:27][C:20]2[S:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)O)cc2c1
Yield: 85.6 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid (0.280 g, 0.619 mmol) is reduced using NaBH4 (14 mg, 0.376 mmol) analogous to Example 2 to afford the title compound (0.241 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Nc1c(F)cc(Br)cc1F
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 4-bromo-2,6-difluoroaniline (10 g, 48 mmol) in DCM (15 mL) was added ethyl 3-chloro-3-oxopropanoate (6.8 mL, 53 mmol) and DIEA (9.2 mL, 53 mmol) and the reaction mixture stirred for 1 h. The reaction mixture was partitioned between H2O and DCM and the layers separated. The DCM portion was washed with satd. NH4Cl and H2O then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to give Compound 90a (10 g, 65% yield). LCMS=1.60 min using analytical method (Q), 321.9 (M+H). 1H NMR (500 MHz, CDCl3) δ 8.89 (br. s., 1H), 7.20-7.15 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 1.36-1.31 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17]>>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16]([N:18]1[CH2:19][CH2:20][CH:21]([OH:24])[CH2:22][CH2:23]1)=[O:17]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC(Cc1cccc(Cl)c1)C(=O)N1CCC(O)CC1
Product: O=C(NC(Cc1cccc(Cl)c1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-1-(4-hydroxy-piperidin-1-yl)-3-(3-chloro-phenyl)-propan-1-one. mp 98° C. dec.
Reaction SMILES: [C:1]([C@@H:4]([C@H:8]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9]1)[CH2:5][CH:6]=[CH2:7])([OH:3])=O.Cl.[CH2:17]([O:24][C:25](=[O:32])[C@H:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[NH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@@H:26]([NH:27][C:1](=[O:3])[C@@H:4]([C@H:8]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9]1)[CH2:5][CH:6]=[CH2:7])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: C=CC[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Agent: Cl
Product: C=CC[C@@H](C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)C)[C@@H]1OC(C)(C)OC1=O
Yield: 86.8 %

Procedure:
According to the method of Preparation 2, (4S)-4-[(1R)-1-carboxy-but-3-enyl]-2,2-dimethyl-1,3-dioxolan-5-one (Preparation 14b)(2.39 g, 11.20 mmol) was reacted with L-tert-leucine benzyl ester hydrochloride (3.03 g, 11.76 mmol) for 1 h at 4° C. and then 17 h at 20° C. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate (200 mL), washed with 0.5M aqueous sodium dihydrogenphosphate (2×200 mL), 5% saturated sodium bicarbonate (200 mL), water, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate 10:1 to 1:1) to give (2R)-N-[(1S)-1-[(benzyloxy)carbonyl]-2,2-dimethylpropyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]pent-4-enamide (4.06 g, 87%), as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:13]=[C:14]=[O:15])([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:11])=[CH2:10])[CH:4]=1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>CC(C)([O-])C.[K+].CCCCCC>[CH3:17][C:16]([O:20][C:14](=[O:15])[NH:13][C:2]([CH3:1])([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:11])=[CH2:10])[CH:4]=1)[CH3:12])([CH3:19])[CH3:18]
Reactant: CC(C)(C)O
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Product: C=C(C)c1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Into a 3-neck, 10 L round bottom flask equipped with a mechanical stirrer, condenser, and a nitrogen inlet was placed α,α-dimethyl-m-isopropenylbenzyl isocyanate (1083 g, 5.38 mol), hexane (6 L), and t-butyl alcohol (398.8 g, 5.38 mol). While the mixture was stirred at room temperature, potassium t-butoxide (18.0 g, 160 mmol) was added in portions. Throughout the addition the reaction temperature increased to 50° C. The reaction was complete within an hour. The reaction mixture was washed with water (5 L), and thereafter, the organics were separated from the aqueous layer. The organics were dried over magnesium sulfate, filtered, and evaporated to yield a yellow-brown semi-solid. Recrystallization from hexane afforded essentially pure {1-methyl-1-[3-(1-methylethenyl)phenyl]ethyl}carbamic acid 1,1-dimethylethyl ester (1193 g, 81% isolated yield), as shown by proton and carbon-13 NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4]1.[Li]CCCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>C1COCC1>[CH3:1][O:2][CH:3]1[CH:12]([B:18]([OH:23])[OH:19])[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: COC1CCc2ccccc2C1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1Cc2ccccc2CC1B(O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A −78° C. solution of 10.0 g (61.6 mmol) of 6-methoxy-5,6,7,8-tetrahydronaphthalene in 75 mL of THF was treated in a dropwise manner with 42.0 mL (67.2 mmol) of 1.6 M n-BuLi in hexanes. The mixture was stirred for 1 hr and was treated with 14.8 mL (64.1 mmol) of triisopropyl borate. The reaction was allowed to warm slowly to 0° C. and was stirred at this temperature for 0.5 hr. The reaction was quenched by the careful addition of 120 mL of aq 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford a white solid which was used in part B without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([OH:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([O:28][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: OC1CN(Cc2ccccc2)CCC1c1cccc(OCc2ccccc2)c1
Product: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-piperidin-3-ol with 2-bromomethylnaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless resin; MS: 514 (M+H)+.
Reaction SMILES: C[O-].[Na+].C([O:6][C:7](=O)[CH:8]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9](OCC)=[O:10])C.Cl.[CH:23]([NH2:25])=[NH:24]>CO>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([C:8]2[C:9]([OH:10])=[N:24][CH:23]=[N:25][C:7]=2[OH:6])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2c(O)ncnc2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methylate (17 g) was dissolved in methanol (600 ml) at 0° C. 2-p-Tolyl-malonic acid diethyl ester (24.5 ml, commercially available from Aldrich), dissolved in 150 ml methanol, was added within 30 min. Stirring was continued for 1 h while slowly warming the mixture to rt. Formamidine hydrochloride (9.9 g, commercially available from Fluka) was added and stirring was continued for 16 h. The solvent was evaporated and 2 M hydrochloric acid (200 ml) was added to the residue followed by slow addition of 10 M sodium hydroxide to adjust the pH to 5. The precipitated product was filtered off and washed subsequently with water and diethylether and dried to give 5-p-tolyl-pyrimidine-4,6-diol (17.7 g). 1H-NMR (d6-DMSO): 8.0(s, 1H); 7.4(d, 2H); 7.1(d, 2H); 2.25(s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[N:12]=[C:13](C4C=CC(C5(NC(=O)OC(C)(C)C)CCC5)=CC=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:5]=3[C:4]=2[N:3]=1>C(O)(C(F)(F)F)=O>[C:16]1([C:14]2[CH:13]=[N:12][C:6]3[CH2:7][CH2:8][C:9]4[CH:10]=[N:11][C:2]([NH2:1])=[N:3][C:4]=4[C:5]=3[CH:15]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3nc(N)ncc3CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc2c(n1)-c1cc(-c3ccccc3)cnc1CC2
Reaction time: 0.01 h
Yield: 38.4 %

Procedure:
Tert-butyl (1-(4-(2-amino-9-phenyl-5,6-dihydropyrido[2,3-h]quinazolin-8-yl)phenyl)cyclobutyl)carbamate (10 mg, 0.019 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (2 mg, 20% yield). 1H NMR (500 MHz, d6-DMSO) 8.04 (br s, 2H), 8.31 (s, 1H), 8.23 (s, 1H), 7.40 (d, 2H), 7.35 (d, 2H), 7.29 (m, 3H), 7.20 (m, 2H), 3.13 (t, 2H), 2.94 (t, 2H), 2.56 (m, 4H), 2.07-2.19 (br m, 1H), 1.74-1.85 (br m, 1H). LCMS (Method A): RT=3.58 min, M+H+=420.