Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1C(O)=O.CN1CCN(C2C3=CC=CN3CC3C=CC=CC=3N=2)CC1>C(Cl)Cl>[NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1
Reactant: Nc1ccccc1Cn1cccc1C(=O)O
Agent: CN1CCN(C2=Nc3ccccc3Cn3cccc32)CC1
Solvent: ClCCl
Product: Nc1ccccc1Cn1cccc1

Procedure:
1-(o-Aminobenzyl)-2-pyrrolecarboxylic acid, prepared by hydrolysis of 1-(o-aminobenzyl)-2-pyrrolecarbonitrile (Example 1) with potassium hydroxide (Example 1), is heated above its melting point for several minutes (245°-250° C.). After the evolution of gases ceases the residue is cooled, taken up in methylene chloride, and a small amount of precipitate is filtered. The filtrate is evaporated and the residue is crystallized with the aid of petroleum ether to give 1-(o-aminobenzyl)pyrrole.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=O.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:10].CC[O-].[Na+].Cl>O.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:9]([O:11][C:12]([C:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2][N:3]2[CH2:7][CH2:6][CH2:5][C:4]=12)=[O:22])[CH3:10]
Reactant: NN1CCCC1=O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2ccccc2)nn2c1CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
To a solution of 1-amino-pyrrolidine-2-one hydrochloride (3.8 g, 27.8 mmol) (WO 02/094833) add ethylbenzoylacetate (4.3 mL, 25 mmol) followed by pyridine (10 mL) at room temperature under nitrogen. Stir the mixture at room temperature for 20 hours and then, dilute with water (50 mL) and extract with toluene (2×50 mL). Dry the combined organic layers (MgSO4) and concentrate in vacuo to give a brown oil, 6.23 g, 82% yield, and treat with NaOEt (freshly prepared, 3.1 g, 45.4 mmol, 2 equiv) in toluene at 120° C. for 8 hours. Cool the mixture to room temperature and add water (100 mL) and concentrated HCl until a pH of 4 is reached. Extract the mixture with EtOAc (3×200 mL) and dry (MgSO4) the combined organic layers and concentrate in vacuo. Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield. MS(ES+): m/z=257.1 (M+H)+
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:12]=3)[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.COCCOC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[NH:12][N:13]=[CH:14][N:15]=4)[CH:9]=3)[NH:4][N:3]=2)=[CH:45][CH:44]=1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 60 °C
Yield: 11.3 %

Procedure:
A mixture of 2-{3-bromo-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazolyl}perhydro-2H-pyran (300 mg, 0.508 mmol), 4-trifluoromethylphenylboronic acid (144 mg 0.758 mmol, 1.49 equiv.), [1,1′-bis(diphenylphosphino)-ferrocene}dichloropalladium (II) complex with dichloromethane (Aldrich), 41.5 mg (0.0508 mmol, 0.100 equiv.), 2.53 mL of anhydrous DME, and powdered potassium phosphate (K3PO4, 535 mg, 2.52 mmol, 4.96 equiv.) were refluxed for 5 days. The reaction was diluted with CH2Cl2, washed with 2×sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel using 30–40% EtOAc in hexanes. To the purified material was added 5.00 mL of MeOH, and 5.00 mL of 6.0 N aq. HCl. The mixture was heated at 60° C. for 24 h. The reaction mixture was filtered. The solid was further purified by silica gel chromatography using EtOAc affording the title compound (69.3 mg). Further purification by prep HPLC afforded the title compound (18.9 mg, 11.3% yield): 1H NMR (CDCl3/CD3OD) δ 8.74 (s, 1H), 8.41–7.97 (m, 4H), 7.78 (d, 2H), 7.66 (d, 1H); ES-MS (m/z) 330 [M+1]+.
Reaction SMILES: CC1SC(NC(C2C=CC(N3CCC(C4C=CC=C(C(F)(F)F)C=4)CC3)=NC=2)=O)=NC=1C1C=CC=CC=1.CC1SC(NC([C:47]2[CH:48]=[CH:49][C:50]([N:53]3[CH2:58][CH2:57][C:56]([OH:65])([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH2:55][CH2:54]3)=[N:51][CH:52]=2)=O)=NC=1C1C=CC=CC=1.ClC1C=CC(C(NC2SC(C)=C(C3C=CC=CC=3)N=2)=O)=CN=1.C1(C2(O)CCNCC2)C=CC=CC=1>>[OH:65][C:56]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:55][CH2:54][N:53]([C:50]2[CH:49]=[CH:48][CH:47]=[CH:52][N:51]=2)[CH2:58][CH2:57]1
Reactant: Cc1sc(NC(=O)c2ccc(N3CCC(O)(c4ccccc4)CC3)nc2)nc1-c1ccccc1
Agent: Cc1sc(NC(=O)c2ccc(Cl)nc2)nc1-c1ccccc1
Agent: Cc1sc(NC(=O)c2ccc(N3CCC(c4cccc(C(F)(F)F)c4)CC3)nc2)nc1-c1ccccc1
Agent: OC1(c2ccccc2)CCNCC1
Product: OC1(c2ccccc2)CCN(c2ccccn2)CC1

Procedure:
With a method similar to that used for the preparation of 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (5-methyl-4-phenyl-thiazol-2-yl)-amide, 4-hydroxy-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (5-methyl-4-phenyl-thiazol-2-yl)-amide was prepared from 6-chloro-N-(5-methyl-4-phenyl-thiazol-2-yl)-nicotinamide and 4-phenyl-piperidin-4-ol. LCMS calcd for C27H26N4O2S (m/e) 470, obsd 471 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([NH:13][CH3:14])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[OH:2][C:3]1[CH:12]=[C:11]([NH:13][CH3:14])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1cc(OC)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CNc1cc(O)c(C(=O)OC)cc1[N+](=O)[O-]
Yield: 106533.5 %

Procedure:
The title compound was prepared following the procedure described for Step-5 of Intermediate-1 using methyl 2-methoxy-4-(methylamino)-5-nitrobenzoate (4.00 g, 0.0166 mmol), anhydrous aluminium chloride (6.64 g, 0.0499 mmol) and EDC to afford 4.00 g of crude desired product. 1HNMR (DMSO-d6): δ 2.93 (d, J=5.1 Hz, 3H), 3.86 (s, 3H), 6.28 (s, 1H), 8.48 (bs, 1H), 8.59 (s, 1H), 11.15 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[C:18]3[S:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[CH:23][C:17]=3[N:16]=[CH:15]2)=[CH:10][C:9]=1[O:31][CH3:32].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:21][C:18]3[C:19](=[O:20])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([NH:7][S:39]([C:36]5[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=5)(=[O:41])=[O:40])=[C:9]([O:31][CH3:32])[CH:10]=4)[CH:15]=[N:16][C:17]=3[CH:23]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A pyridine (1 mL) solution of 3-(4-Amino-3-methoxyphenyl)-6-(4-chloro-phenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.050 g, 0.0013 mol, the preparation of which is found in Example K13) and p-toluenesulfonyl chloride and was agitated overnight at RT, then diluted with water and filtered to give a white powder (0.056 g 81%). LCMS m/z 538 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.70 (d, 2H), 7.60 (d, 2H), 7.38 (d, 2H), 7.35 (d, 1H), 7.20 (s, 1H), 7.05 (d, 1H), 3.62 (s, 3H), 2.41 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].C([O-])(=O)C.[Na+].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: COC(OC)OC
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reaction time: 8 h

Procedure:
5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde was dissolved in dichloroethane with 1-methylsulfonylpiperazine hydrochloride (1.45 eq), sodium acetate (1.45 eq), and trimethylorthoformate (1.45 eq). The solution was stirred overnight. Sodium triacetoxyborohydride (1.35 eq) was added and after three hours at room temperature the reaction was quenched with saturated sodium bicarbonate solution. The aqueous was extracted with methylene chloride, dried with sodium sulfate and purified by silica gel chromatography to give 5-chloro-2-((4-methylsulfonylpiperazin-1-yl)methyl)-7-morpholinothiazolo[5,4-d]pyrimidine.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([NH:13][C:14]([NH2:16])=[NH:15])[S:12][C:6]=2[CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[NH:13]([C:11]1[S:12][C:6]2[CH2:5][NH:4][CH2:9][CH2:8][C:7]=2[N:10]=1)[C:14]([NH2:16])=[NH:15]
Reactant: CC(=O)N1CCc2nc(NC(=N)N)sc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)Nc1nc2c(s1)CNCC2
Yield: 68 %

Procedure:
5-Acetyl-2-guanidino-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine (232.4 mg, 0.971 mmol) was mixed with ethanol (7 ml) and treated with an aqueous solution of sodium hydroxide (1.98 ml of a 1.46M solution, 2.9 mmol). The reaction mixture was heated to 81° for 72 hours, then concentrated in vacuo; the residue was purified by column chromatography (eluant: 89:10:1 of chloroform:methanol: concentrated ammonium hydroxide) to provide the title product as an oil (129.9 mg, 0.66 mmol, 68% yield).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[C:17]([CH3:33])=[C:16]([Cl:34])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[C:17]=1[CH3:33]
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCOC1=O
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1N1CCOC1=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (6.3 mg, 0.032 mmol), 3-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]-1,3-oxazolidin-2-one (10 mg, 0.03 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.057 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min, to give the desired. LCMS calculated for C23H21ClFN6O2 (M+H)+: m/z=467.1. found: 467.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[O:17][N:16]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>CC(O)(C)C>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:38]3[CH2:39][CH2:40][CH:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]3)[CH:7]=2)[N:10]=[C:11]([C:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[O:17][N:16]=2)[N:12]=1
Reactant: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(Cl)c1
Reactant: CS(=O)(=O)C1CCNCC1
Solvent: CC(C)(C)O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(N2CCC(S(C)(=O)=O)CC2)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)isoxazole (50 mg, 0.12 mmol) in t-BuOH (0.5 mL), was added 4-(methylsulfonyl)piperidine (75 mg, 0.46 mmol). The mixture was stirred at 140° C. for 16 h, then cooled to RT and purified by prep-HPLC (Mobile phase: A=10 mM ammonium bicarbonate/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give the title compound as a white solid; MS (ES+) C25H25F3N6O4S requires: 562. found: 563 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=5.0 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.03 (s, 1H), 6.43 (m, 2H), 5.30 (s, 2H), 4.47 (bd, J=13.4 Hz, 2H), 3.07 (m, 1H), 2.97-2.81 (m, 5H), 2.50 (s, 3H), 2.20 (bd, J=12.4 Hz, 2H), 1.86-1.79 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([NH2:18])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]#[N:18])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Product: N#C[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxamide [see Preparation 50] and oxalyl chloride. The crude product was purified by column chromatography on silica gel eluting with dichloromethane to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarbonitrile as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl[CH2:19][CH2:20][CH2:21][OH:22]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: OCCCCl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(OCCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
Into a 300 ml flask, 20 g (102.4 mmol) of 4-cyano-4'-hydroxybiphenyl, 140 ml of ethanol and a NaOH aqueous solution (7.48 g (132.2 mmol) of NaOH/40 ml of water) were added. The mixture was stirred at 80° C. for 10 minutes, and then 10.66 g (112.8 mmol) of 3-chloro-1-propanol was added thereto. The mixture was heated and refluxed for 18 hours. Ethanol was distilled off. Then, 300 ml of water was added to the reaction solution, and the mixture was neutralized with hydrochloric acid. Precipitated crystals were collected by filtration. Then, 1200 ml of toluene was added thereto, and the toluene layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Further, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 5.34 g (yield: 21%) of 4-cyano-4'-(3-hydroxypropoxy)biphenyl (7) as colorless crystals.
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][C@@H:10]([CH3:25])[CH2:11][C:12]1[C:20]2[CH:19]=[C:18]([OH:21])[CH:17]=[CH:16][C:15]=2[N:14]2[CH2:22][CH2:23][CH2:24][C:13]=12)(C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][O:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:22][CH2:23][CH2:24][C:13]3=[C:12]([CH2:11][C@@H:10]([NH2:9])[CH3:25])[C:20]=2[CH:19]=1
Reactant: C[C@@H](Cc1c2n(c3ccc(O)cc13)CCC2)NC(=O)OC(C)(C)C
Reactant: COCCOCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCCOc1ccc2c(c1)c(C[C@H](C)N)c1n2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
25 mg sodium hydride 55-65% in oil was added to a solution of 165 mg (S)-[2-(6-hydroxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester in 1.5 mL N,N-dimethylformamide. The mixture was stirred at room temperature for 30 min, then 120 mg 3-(methoxyethoxy)propyl bromide was added added and the reaction mixture was stirred at room temperature for an additional 22 h. The reaction mixture was distributed between water and ethyl acetate. The phases were separated, the organic phase washed with water, 10% citric acid, 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate=4:1. The product fractions were evaporated and the residue taken up in 4.0 mL of a 2.16 M solution of hydrochloric acid in ethyl acetate. The mixture was stirred at room temperature for 1 h, the solid collected by filtration, neutralised with aqueous ammonium hydroxide and purified by chromatography on silica gel with dichloromethane:methanol:aqueous ammonium hydroxide=90:9:1. The product fractions were dried over magnesium sulfate and evaporated to yield 80 mg (S)-2-{6-[3-(2-methoxy-ethoxy)-propoxy]-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl}-1-methyl-ethylamine as light brown oil. MS: M+H=347.5; M+H−NH3=330.4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5](C)=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.OCC1OC=CC(=O)C=1O.C(Br)C1C=CC=CC=1>>[OH:1][CH2:2][C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Agent: BrCc1ccccc1
Agent: O=c1ccoc(CO)c1O
Product: O=c1ccoc(CO)c1OCc1ccccc1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 7.1 g (50 mmol, 1 eq.) of 2-hydroxymethyl-3-hydroxy-pyran-4(1 H)-one and 9.5 g benzyl bromide (55 mmol, 1.1 eq.) to yield the crude product as an organe oil. Further purification by column chromatography on silica gel (eluant: 10% CH3OH/90% CHCl3) furnished the pure product (9.4 g, 81%) as a bright yellow oil. (Looker and Clifton (1986).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][NH:14][CH:15]([CH2:21][O:22]C(=O)C)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]>[NH4+].[OH-].CO>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:13][NH:14][CH:15]([CH2:21][OH:22])[C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(CNC(COC(C)=O)C(=O)N(C)C)C(=O)OC(C)(C)C)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1cccc(C(CNC(CO)C(=O)N(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
2-[2-(3-Butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-3-acetoxy-N,N-dimethylpropan-amide (0.19 g, 0.42 mmol) was dissolved in 3% NH4OH/MeOH (15 ml) and stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (silica, petroleum ether:EtOAc from 7:3 to 3:7) affording the title compound (0.13 g, 66% yield) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: CCN(CC)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and Diethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-diethyl-amine, MS: 373 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH3:34])=[O:32])=[C:5]([CH3:35])[CH:4]=1)#[N:2].[CH2:36](N)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH2:34][CH3:36])=[O:32])=[C:5]([CH3:35])[CH:4]=1)#[N:2]
Reactant: CCN
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C
Product: CCNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C

Procedure:
The title compound is prepared in analogy to 4-(4-cyano-2-methylphenyl)-N-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxamide (example 73), replacing methylamine with ethylamine as reagent. Yield: 45 mg; ESI mass spectrum [M+H]+=497; Retention time HPLC: 0.77 min (X012_S01).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([OH:11])[N:6]=[C:5]1[S:12][CH3:13]>[OH-].[Na+]>[CH3:3][N:4]1[C:9](=[O:10])[C:8]([Br:1])=[C:7]([OH:11])[N:6]=[C:5]1[S:12][CH3:13]
Reactant: BrBr
Reactant: CSc1nc(O)cc(=O)n1C
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(O)c(Br)c(=O)n1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
16 g (0.1 mol) of bromine were added to a solution of 17.2 g (0.1 mol) of 1-methyl-2-methylthio-4-hydroxy-6-oxo-1,6-dihydro-pyrimidine in 110 ml of 1 N sodium hydroxide solution at room temperature. After the end of the addition, the batch was stirred for a further 0.5 hour and was then cooled to 5° C. The product which had precipitated was filtered off and rinsed with water. 18 g (76% of theory) of 1-methyl-2-methylthio-4-hydroxy-5-bromo-6-oxo-1,6-dihydro-pyrimidine were thus obtained in the form of pale yellow crystals of melting point 184° C. (with decomposition).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:38]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:41]([CH3:43])[CH3:42])[O:33][CH2:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1)([CH3:39])[CH3:40]
Reactant: CC(C)[Si](OCCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.6 %

Procedure:
To a solution of Intermediate A (122 mg, 0.75 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 60 mg, 1.5 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 66b (315 mg, 0.75 mmol) in DMF (2.5 mL) was added and the mixture stirred at 60° C. for 1.5 h. The cooled mixture was diluted with water and extracted with DCM (5×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (180 mg, 42%). LCMS (Method 3): Rt 3.35 min, m/z 564 [MH+].