Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[F:27][C:28]([F:40])([F:39])[CH:29]([CH3:38])[O:30][C:31]1[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:34]3[CH:35]=[N:36][C:31]([O:30][CH:29]([CH3:38])[C:28]([F:40])([F:27])[F:39])=[CH:32][CH:33]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(Oc1ccc(N)cn1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cn1)C(F)(F)F

Procedure:
Off-white crystalline solid.MS (ESI): 518.0 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine.
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[CH3:24])=[C:10]([O:25][Si](C(C)(C)C)(C)C)[C:9]=1[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34].[N:39]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[CH3:24])=[NH:39])=[C:10]([OH:25])[C:9]=1[S:33]([N:36]([CH3:37])[CH3:38])(=[O:35])=[O:34]
Reactant: Cc1c(F)cccc1N=C=Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Reactant: N#CN
Reactant: N#CNC(=N)N
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cccc1NC(=N)N(C#N)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1O
Yield: 44 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-methyl-3-fluorophenyl)carbodiimide (320 mg, 0.64 mmol), cyanamide (108 mg, 2.56 mmol) and N,N-diisopropylethylamine (99 mg, 0.77 mmol) were reacted, followed by desilylation with Cesium fluoride (117 mg, 0.77 mmol) to form the desired product (120 mg, 44%). EI-MS m/z 426.2 (M+). 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 2.86 (s, 6H), 7.09 (m, 3H), 7.22 (m, 1H), 7.56 (d, 1H), 8.82 (s, 1H), 9.10 (s, 1H), 10.51 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:13])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]2[N:11]([CH3:21])[C:12](=[O:13])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5](=[O:7])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCNC(=O)Nc1cnc(Cl)cc1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCn1c(=O)c2cc(Cl)ncc2n(C)c1=O
Temperature: 40 °C
Yield: 4.8 %

Procedure:
To a solution of 2-chloro-5-(3-(3-methoxy-3-oxopropyl)ureido)isonicotinic acid (33.8 g, 112 mmol) in acetone (386 mL) was added K2CO3 (46.4 g, 336 mmol) followed by CH3I (95.4 g, 672 mmol). The reaction was heated in a sealed tube at 40° C. for 24 h, cooled to RT, concentrated then diluted with EA (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 2:1) to give methyl 3-(6-chloro-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (1.6 g, 11% yield) as a yellow solid. LCMS: MH+ 298 and TR=2.857 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:9]=[C:10]([CH:14]=[C:15](I)[CH:16]=1)[C:11]([OH:13])=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[C@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[C@@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([C:8]4[CH:9]=[C:10]([CH:14]=[C:15]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])[CH:16]=4)[C:11]([OH:13])=[O:12])[C:28]3=[O:36])[CH2:26]2)=[CH:23][CH:24]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: O=C1CCCN1
Product: O=C(O)c1cc(N2CCCC2=O)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 92 starting from 2-pyrrolidone, 3-bromo-5-iodo-benzoic acid (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C27H21ClN2O4: 472, observed (M+H)+: 4731.2 1HNMR (400 MHz, MeOD-d4) δppm 2.18-2.35 (m, 4 H) 2.67 (t, J=8.08 Hz, 2 H) 3.35-3.39 (m, 1 H) 4.05 (t, J=7.07 Hz, 2 H) 6.16 (d, J=7.07 Hz, 1 H) 6.82 (t, J=7.45 Hz, 1 H) 6.97 (d, J=7.33 Hz, 1 H) 7.12-7.20 (m, 1H) 7.34 (q, J=8.67 Hz, 4 H) 7.95 (s, 1 H) 8.20 (t, J=1.89 Hz, 1 H) 8.33 (s, 1 H).
Reaction SMILES: [Na].[CH2:2](C#N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]([O:15]CC)(=O)[CH2:12][CH3:13]>>[CH2:2]([C:11]([CH2:12][CH3:13])=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CC
Agent: [Na]
Product: CCC(=O)Cc1ccccc1
Yield: 53.3 %

Procedure:
In a 2-liter flask provided with a thermometer, stirrer, dropping funnel and reflux condenser 600 ml of absolute alcohol are treated portionwise while stirring with 30 g of sodium metal and the mixture is held at reflux temperature until the metal has dissolved. Within 0.5 hour there is added dropwise to the boiling solution a mixture of 117.2 g of benzyl cyanide and 153.2 g of ethyl propionate and the mixture is heated for a further 3 hours. The alcohol is then distilled off and there are added 300 ml of toluene, followed by 250 ml of ice/water. The aqueous phase is separated, washed with 300 ml of toluene and then 540 g of 96% sulphuric acid are added. The mixture is held at reflux temperature until the evolution of carbon dioxide ceases, cooled, diluted with 250 ml of ice/water and extracted with two 300 ml portions of toluene. The toluene extracts are washed with water, with 10% sodium carbonate solution and again with water, dried over sodium sulphate and evaporated. Distillation gives 79 g of ethyl benzyl ketone of boiling point 69° C./3 mmHg; nD20 =1.5109; yield 53%.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[C:42]([CH3:43])=[C:41]([CH3:44])[N:40]([CH3:45])[C:39](=[O:46])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[C:42]([CH3:43])=[C:41]([CH3:44])[N:40]([CH3:45])[C:39](=[O:46])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1c(Br)cc(=O)n(C)c1C
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1c(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(=O)n(C)c1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-1,5,6-trimethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.187 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.15 (s, 3H), 1.32 (m, 3H), 1.52 (m, 3H), 1.72 (s, 1H), 2.18 (m, 3H), 2.19 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H), 4.12 (m, 2H), 5.66 (m, 1H), 6.16 (s, 1H), 6.53 (s, 1H), 6.98 (m, 2H), 7.23-7.34 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:23]=[O:24])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].CCCCCC>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:23][OH:24])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccs1
Yield: 90.6 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-thienyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (940.68 mg) in 99% ethanol (30 ml) was gradually added sodium borohydride (113.5 mg) under stirring and this was further stirred at room temperature for 2 hours. After removal of ethanol, the residue was extracted with ethyl acetate and the extract was washed twice with water and then dried. The solvent was removed from the extract to give a pale yellow oil. The oil was pulverized with n-hexane. The powder was dissolved in ethyl acetate. After collecting by filtration of the insoluble product, to the filtrate was added n-hexane and the mixture was allowed to stand in refrigerator. The appearring crystals were collected by filtration to give pale yellow granules (857.2 mg) of diethyl 2-methyl-4-(2-thienyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 125° to 126° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(C#N)ccc1Br
Product: COc1ccc(-c2ccc(C#N)cc2C)cc1
Yield: 80 %

Procedure:
4-Bromo-3-methylbenzonitrile and 4-methoxyphenylboronic acid were processed as described in Example 164A to provide the title compound (80% yield). 1HNMR (300 MHz, CDCl3) δ2.40 (3H), 3.73 (s, 3H), 6.84-7.60 (m, 7H); MS (DCI) m/z 224 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C[O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17]>>[OH:11][CH:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][NH:17][C@H:16]([C:15]([OH:19])=[O:14])[CH3:18]
Reactant: Fc1cc(F)cc(C2CO2)c1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: C[C@H](NCC(O)c1cc(F)cc(F)c1)C(=O)O

Procedure:
Following General Procedure EB and reacting 2-(3,5-difluorophenyl)-1,2-epoxyethane (Example EC1) and L-alanine methyl ester hydrochloride (Bachem), the title compound was isolated after flash chromatography with 3:1 to 1:1 (gradient) hexanes/ethyl acetate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[NH:15][C@@H:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[C@H:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])[CH2:4][CH2:3]1.C=O.[C:41]([BH3-])#N.[Na+].C(OCC)(=O)C>C(#N)C.O>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@@H:11]2[N:15]([CH3:41])[C@@H:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[C@H:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])[CH2:4][CH2:3]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@H]2CC[C@H](O)CC2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@@H](c2cccc(Cl)c2F)[C@@H]1C(=O)NC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a suspension of 0.50 g (0.89 mmol) of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexyl)-amide in 18.0 mL of acetonitrile under argon, were added 0.89 mL (0.97 mmol) of a 36.5% solution of formaldehyde in water, followed by 65 mg (0.98 mmol) of sodium cyanoborohydride. The resulting solution was stirred at room temperature for 2 hours, upon which it was poured into 50 mL of ethyl acetate. The aqueous phase was separated and the organic phase was washed with a saturated solution of sodium hydrogencarbonate. The latter aqueous phase was reextracted with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue (0.52 g) was purified by chiral HPLC chromatography on a Kromasil C18 column (1100 g batch 4680, 10 μm, 7.65×35 cm), eluting solvent: acetonitrile/water 40/60 v/v+0.1% trifluoroacetic acid; flow: 250 mL/min. The collected solution was treated with sodium hydrogencarbonate up to pH 8 and then extracted 3 times with 200 mL of ethyl acetate. The combined organic extracts were washed twice with 100 mL of water, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was then dried in a dessicator under reduced pressure for 16 hours. 0.17 g of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-1′-methyl-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-hydroxy-cyclohexyl)-amide was obtained as a white solid. mp: 188° C. (Kofler); LC-MS:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:38])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](OCC(OC)=O)=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[OH-:39].[Na+].[CH3:41][OH:42].[ClH:43]>O>[ClH:43].[CH3:1][C:2]1[NH:3][C:4]([CH3:38])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:3]([CH2:4][CH2:41][OH:42])[CH2:2][CH2:1][OH:39])=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CO
Reactant: COC(=O)COc1ccc(CCOC(=O)C2=C(C)NC(C)=C(C(=O)OC)C2c2cccc([N+](=O)[O-])c2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(N(CCO)CCO)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 0.5 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[2-(4-methoxycarbonylmethoxyphenyl)ethoxycarbonyl]-1,4-dihydropyridine, 0.5 ml 10% aqueous NaOH, and 20 ml of methanol was heated on a steam bath for 20 min. The mixture was diluted with water, acidified with HCl, and extracted with ethyl acetate. The ethyl acetate was dried and evaporated to yield 0.40 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[2-(4-carboxymethylphenyl)ethoxycarbonyl]-1,4-dihydropyridine (1). Calculated for C26H26N2O9.0.5H2O: C-59.17, H-5.36, N-5.52.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.[CH3:60][NH:61][CH2:62][C:63]1[NH:64][C:65](=[O:68])[NH:66][N:67]=1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:61]([CH3:60])[CH2:62][C:63]1[NH:64][C:65](=[O:68])[NH:66][N:67]=1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNCc1n[nH]c(=O)[nH]1
Agent: CN
Agent: Cl
Product: CN(Cc1n[nH]c(=O)[nH]1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with 5-[(methylamino)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one, (prepared using the method of T. Ladduwahetty et al., J. Med. Chem 1996, 39, 2907-2914) the title compound was obtained. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C13H14BrN6O4S (M+H+): 428.9975. Found 428.9974.
Reaction SMILES: [CH3:1][CH:2]([CH2:53][CH3:54])[C@H:3]([NH:14][C:15]([C@:17]1([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42](=[O:51])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:37]([CH3:40])[CH2:38][CH3:39])[CH2:29][C:28]2[C:27]3[C:22](=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH2:19][CH2:18]1)=[O:16])[C:4](=S)[NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Na]>C1COCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][CH:2]([CH2:53][CH3:54])[C@H:3]([NH:14][C:15]([C@:17]1([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42](=[O:51])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:37]([CH3:40])[CH2:38][CH3:39])[CH2:29][C:28]2[C:27]3[C:22](=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH2:19][CH2:18]1)=[O:16])[CH2:4][NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@]1(C(=O)N[C@H](C(=S)NCC2CCOCC2)C(C)CC)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Agent: Cl[Ni]Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@]1(C(=O)N[C@H](CNCC2CCOCC2)C(C)CC)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Reaction time: 0.17 h

Procedure:
0.050 g (0.06 mmol) of (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-thiocarbamoyl]-butyl}-amide were dissolved in 7 mL of THF/Methanol (1:1). 0.123 g (0.52 mmol) of nickel(II)chloride hexahydrate were added at room temperature. The mixture was stirred for 10 min at this temperature. At 0° C. 0.059 g (1.55 mmol) sodium borhydrate were added. Stirring was continued for 18 h at room temperature. The mixture was filtered over silica gel and the silica gel layer was washed with MeOH. The filtrate and washes were combined, concentrated and the residue purified by HPLC.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CN(C=O)C>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([O:16][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)N(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.8 %

Procedure:
To a solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (2.0 g, 9.04 mmol) in DMF (20 mL) was added sodium hydride (1.0 g, 25 mmol). After stirring at RT for 20 min, a solution of N,N-dimethyl carbamoyl chloride (1.9 g, 17.7 mmol) in DMF (5 mL) was added dropwise into the reaction mixture, which was stirred at RT for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice water (400 mL) and extracted with EtOAc (3×200 mL). The organic layer was washed with water (3×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-7% MeOH in DCM) to yield N,N-dimethyl-carbamic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (100 mg). 1H NMR (CD3OD, freebase) δ (ppm): 8.5 (d, 2H), 7.34 (d, 2H), 7.31 (d, 1H), 7.21 (s, 1H), 7.00 (d, 1H), 5.96 (t, 1H), 4.53 (dd, 1H), 4.45 (dd, 1H), 3.49 (t, 2H), 2.98 (m, 2H), 2.95 (m, 5H), 2.92 (s, 3H), 2.77 (s, 3H), 2.39 (s, 3H). Separation by chiral HPLC provided enantiomers 141a and 141b.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:24][O:23][C:22]1[C:2]([C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]=2[CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1ccc(-c2cc3c(cc2OC)N(C)C(=O)CN=C3c2cccc(C#N)c2)cc1
Yield: 53 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used p-methoxyphenyl boronic acid. The title compound (85 mg) was obtained as a white solid, (yield=53%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:29]([C:34](O)=[O:35])[CH2:30][CH2:31][CH2:32][NH2:33])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.ON1C(=O)CCC1=O>[CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:34](=[O:35])[C@H:29]([CH2:30][CH2:31][CH2:32][NH2:33])[N:28]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)O
Reactant: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
D-Homophenylalanine Benzyl ester Tosylate (2.48 g, 5.6 mmol) was suspended in ethyl acetate (25 mL) and a saturated solution of sodium bicarbonate in water was added in portions (25 mL) with stirring at 25° C. The water layer was extracted with ethyl acetate (3×10 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford D-Homophenylalanine Benzyl ester. The ester was dissolved in acetonitile (25 mL). NaNd-bis-Boc-L-Ornithine (2.0 g, 6.0 mmol) was then added followed by N-hydroxysuccinimide (50 mg) and dicyclohexylcarbodiimide (1.28 g, 6.2 mmol). The reaction was stirred at 25° C. for 30 hr, filtered and the filtrate concentrated to dryness to afford crude product. It was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1), which gave the title product (2.80 g) as white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[N:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25]C[CH2:23][CH2:22]1>>[CH2:22]([N:21]([CH2:26][CH3:25])[CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH3:23]
Reactant: NCCCN1CCCCC1
Reactant: O=C(c1ccc(F)cc1)N1CCCC1CN1CCCC1
Product: CCN(CC)CCCNc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
(S)-[4-(3-Diethylamino-propylamino)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from (4-Fluoro-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-piperidino propylamine in a manner substantially similar to Procedure A. MS (APCI+) 399 (M+H)+.